CN110291089B - Protein kinase inhibitors for promoting liver regeneration or reducing or preventing liver cell death - Google Patents

Abstract

The invention relates to MKK4 (mitogen activated protein kinase 4) and its use in promoting liver regeneration or reducing or preventing liver cell death. The MKK4 inhibitor selectively inhibits the protein kinase MKK4 relative to the protein kinases JNK and MKK 7.

Description

Protein kinase inhibitors for promoting liver regeneration or reducing or preventing liver cell death

Technical Field

The present invention relates to protein kinase inhibitors which inhibit mitogen-activated protein kinase 4(MKK4), in particular, which selectively inhibit MKK4 over the protein kinases JNK1 and MKK 7.

Background

Liver disease may be caused by infection, injury, exposure to toxic compounds such as alcohol or drugs, autoimmune processes, genetic defects, and other factors. The liver has a significant regenerative capacity, however, this regenerative capacity may be impaired in disease states and thus may not be sufficient to compensate for the loss of hepatocyte and organ function.

WO 2007/002433 describes compounds that are inhibitors of protein kinases and that are useful in the treatment of diseases and conditions associated with abnormal activity of protein kinases. These compounds are inhibitors of Raf protein kinases, particularly B-Raf and c-Raf and mutations thereof, and are therefore useful in the treatment of cancer. In addition, they are said to inhibit a variety of other protein kinases including c-Jun N-terminal kinases (JNKs), particularly JNK 1. WO 2010/002325 has similar disclosures, and WO2012/109075 and WO2014/194127 disclose modified compounds having Raf protein kinase inhibitory activity. Vin et al refer to two compounds of WO 2007/002433 as B-Raf inhibitors, which inhibit apoptosis through non-target inhibition of JNK signaling. WO2012/136859 discloses compounds which are described as inhibitors of mitogen-activated protein kinase 4(MKK4) and which are useful for the treatment of liver failure, for protecting liver cells from apoptosis and for the regeneration of liver cells. Wuetefeld et al (Cell 153:389-401,2013) describe functional genetic methods for identifying gene targets that can be used to increase hepatocyte regenerative capacity. Specifically, Wuestefeld et al identified the protein kinase MKK4 as a key regulator of liver regeneration and reported that MKK4 inhibition increased liver cell regeneration through compensatory up-regulation of MKK7 and JNK1 dependent ATF2 and ELK1 activation. Based on the findings of the prior art, it has been concluded that MKK4 and JNK1 inhibitors are useful for the treatment of JNK1 mediated diseases. However, failure of these compounds to treat liver disease has been recognized in clinical therapy.

Disclosure of Invention

The problem underlying the present invention is to provide useful inhibitors of MKK4, in particular inhibitors of MKK4 which inhibit MKK4 selectively with respect to MKK7 and JNK 1. Another problem is to provide MKK4 inhibitors, in particular MKK4 inhibitors that selectively inhibit MKK4 over MKK7 and JNK1, which are useful for treating liver diseases, in particular for promoting liver regeneration or reducing or preventing liver cell death.

This problem is solved by providing an MKK4 inhibitor of formula (I) and a compound of formula (Ia).

Accordingly, the present invention relates to MKK4 inhibitors having formula (I) and pharmaceutically acceptable salts, prodrugs, biologically active metabolites, solvates and stereoisomers thereof,

wherein the variables in formula (1) have the following meanings:

R¹is H or alkyl;

R²is H, alkyl, -CF₃、-CH₂-X-(CH₂)_n-Y or CH₂X¹；

X is-N (R)¹⁰) -, -S-, or-O-;

y is as follows:

H，

phenyl optionally substituted with one or two groups independently selected from alkyl, halogen, alkoxy, hydroxy and SO₂An alkyl group, a carboxyl group,

an alkoxy group,

a furyl group, a thienyl group,

thienyl, or

Pyridyl group, and

wherein the group- (CH)₂)_n-optionally substituted with OH;

n is 1, 2 or 3;

X¹is NR¹⁰SO₂-phenyl, wherein the phenyl group is optionally substituted with one or two groups independently selected from: halogen, -OCF3 and alkoxy, or a heterocyclic group selected from the group consisting of piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, said heterocyclic group being capable of being substituted by alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy or carboxy;

A is a bond or a linking group selected from:

-CO-，

-CO-CO-，

-S-，

-SO-，

-SO₂-，

-O-，

-C(＝N-NHR¹⁰)-，

-CH＝，-CONR¹⁰-，

-NR¹⁰CO-，

-NR¹⁰-SO₂-，

-O₂S-NR¹⁰-，

-CO-alkylene-,

-alkylene-CO-,

-alkylene-NR¹⁰CO-，

-OCNR¹⁰-an alkylene group-,

alkylene optionally substituted with one or two groups independently selected from OH and alkoxy,

an alkenylene group, a carboxyl group,

an alkynylene group (an alkinylene group),

-NR¹⁰-，

-alkylene-NR¹⁰-an alkylene group-,

-alkylene-NR¹⁰-,

-NR¹⁰-an alkylene group-,

-alkylene-NR¹⁰SO₂-，

-SO₂NR¹⁰-an alkylene group-,

-alkylene-NR¹⁰SO₂-an alkylene group-,

-alkylene-CONR¹⁰-an alkylene group-,

-alkylene-NR¹⁰CO-alkylene-,

-alkylene-NR¹⁰CONR¹⁰-an alkylene group-,

-alkylene-NR¹⁰CSNR¹⁰-an alkylene group-,

-alkylene-NR¹⁰CONR¹⁰-，

-NR¹⁰CONR¹⁰-an alkylene group-,

-alkylene-NR¹⁰CSNR¹⁰-，

-NR¹⁰CSNR¹⁰-an alkylene group-,

-alkylene-NR¹⁰-alkylene-NR¹⁰-，

-NR¹⁰-alkylene-NR¹⁰-an alkylene group-,

-CO-alkylene-O-,

-O-alkylene-CO-;

q is an aromatic or heteroaromatic 5-or 6-membered monocyclic or aromatic or heteroaromatic 9-or 10-membered bicyclic group, wherein the heteroaromatic group has 1, 2 or 3 heteroatoms independently selected from O, N and S, the monocyclic or bicyclic group being optionally substituted with one, two or three groups independently selected from:

alkyl optionally substituted with one or two substituents independently selected from phenyl, halo-substituted phenyl, halo, OH, CN, -NR ¹⁰R¹⁰Cycloalkyl and heteroaromatic 5-or 6-membered monocyclic groups having 1, 2 or 3 heteroatoms independently selected from O, N and S;

optionally substituted by-NO₂A substituted alkenyl group;

halogen;

a hydroxyl group;

-CHO；

-COOR²²；

-NO₂；

an alkoxy group;

a haloalkoxy group;

a cycloalkoxy group;

an alkylcarbonyloxy group;

alkylthio (alkylthio);

thienylthio (thienylthio);

phenyl optionally substituted with one or two groups independently selected from alkyl, hydroxyalkyl, alkoxy, halo, alkylthio and NR¹⁰R¹⁰；

Phenoxy optionally substituted with halogen;

-CO-alkyl optionally substituted with phenoxy;

-CO-phenyl optionally substituted with halogen or alkoxy;

a heteroaromatic or non-aromatic heterocyclic 5-or 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, said monocyclic group being optionally substituted with one or two groups independently selected from alkyl, haloalkyl, halogen, thioalkyl and phenyl;

-NR¹⁰R¹¹；

-NR¹⁰SO₂R¹²；

-NR¹⁰SO₂R¹³；

-NR¹⁰SO₂NHR¹⁰；

-N＝S(＝O)R¹⁰NR¹⁰R¹⁰；

-O-alkylene-phenyl, wherein the phenyl group is optionally selected from alkyl, haloalkyl, halogen, -SO₂Alkyl, imidazolyl, oxadiazolyl (oxadiazolyl) and CH₂-a piperazinyl group substitution;

-O-alkylene-R¹⁴；

-OCH₂O- (adjacent to Q);

-OCF₂O- (adjacent to Q);

-OCH₂CH₂o- (adjacent to Q);

-O-alkylene-R¹⁵；

-O-alkylene-phenyl, wherein the phenyl is optionally substituted with one, two or three substituents which are independentlySelected from alkyl, halogen, haloalkyl and-CH optionally substituted on the second nitrogen by alkyl₂A piperazinyl group;

indolyl optionally substituted on the nitrogen by alkyl, alkenyl, alkynyl, -CH₂-O-alkylene-phenyl, -SO₂-phenyl, -CONR¹⁰R¹⁶or-SO₂NR¹⁰R¹⁰Substitution;

-NR¹⁰CONR¹⁰R¹⁷；

-NR¹⁰COR¹⁸；

-NR¹⁰COOR¹⁰；

-CO-NR¹⁰R¹⁹；

-alkylene-NR¹⁰SO₂R²⁰；

-SO₂R²¹(ii) a And

-alkylene-NR¹⁰COR²³；

R⁴Is a compound of formula (I) in the formula (H),

the halogen(s) are selected from the group consisting of,

CN，

NO₂，

an alkyl group, a carboxyl group,

phenyl optionally substituted by one, two or three groups independently selected from NR²⁶R²⁶、 -COR²⁴Alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkylsulfonyl, CN, NO₂Alkenyl groups and carboxyl-substituted alkenyl groups,

-alkylene-NR¹⁰SO₂-R²⁷，

A heteroaromatic or non-aromatic heterocyclic 5-or 6-membered monocyclic or heteroaromatic 9-or 10-membered bicyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, said monocyclic or bicyclic group being optionally substituted with one or two groups independently selected from:

an alkyl group, a carboxyl group,

an alkoxy group,

the halogen(s) are selected from the group consisting of,

a cycloalkyl group,

-CHO，

a phenyl carbonyl group,

phenylcarbonyl, wherein the phenyl group is substituted with halogen or hydroxy,

A halogenated alkyl-carbonyl group,

NR¹⁰R¹⁰，

a heteroaromatic or non-aromatic heterocyclic 5-or 6-membered monocyclic radical having 1, 2 or 3 heteroatoms independently selected from O, N and S, which monocyclic radical can in turn be substituted by alkyl,

alkyleneoxyphenyl (alkylphenoxyphenyl),

an alkylene-thiophenyl group, which is a thio group,

phenylalkyl, wherein the phenyl group is optionally substituted by alkyl or alkoxy,

-alkylene-COOR¹⁰Or is or

Alkenyl optionally substituted with phenyl or halogen-substituted phenyl;

R⁵is composed of

H，

The halogen(s) are selected from the group consisting of,

alkyl optionally substituted with one or two groups independently selected from alkoxy, NR¹⁰R¹⁰、 -COOR¹⁰And an oxadiazolyl group, and a oxadiazole group,

an alkoxy group,

an alkenyl group, which is a radical of an alkenyl group,

an alkynyl group (alkinyl),

phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with one, two or three groups independently selected from: alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkylthio, alkylsulfonyl-NR¹⁰-、NR¹⁰R¹⁰、R¹⁰R¹⁰NSO₂-, alkoxy, benzyloxy, haloalkoxy, -OCH₂O- (methylenedioxy group attached to adjacent positions of phenyl ring), -OCH₂CH₂O- (ethylenedioxy group attached to adjacent position of phenyl ring), NO₂、-COOR¹⁰、-CONR¹⁰R¹⁰CN, alkylcarbonyl-NR¹⁰-, alkenyl anda carboxy-substituted alkenyl group,

Phenylalkenyl, wherein the phenyl is optionally substituted with one, two or three groups independently selected from OH, alkoxy and-CONR¹⁰R¹⁹；

NR¹⁰R²⁸，

A heteroaromatic or non-aromatic heterocyclic 5-or 6-membered monocyclic or heteroaromatic 9-or 10-membered bicyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, said monocyclic or bicyclic group being optionally substituted with one or two groups independently selected from: alkyl, alkoxy, morpholinyl, piperazinyl, oxadiazolyl and phenylcarbonyl wherein the phenyl is optionally substituted by alkyl, halo or alkoxy;

R⁶is H, alkoxy, NR¹⁰R¹⁰or-NR¹⁰-phenyl, wherein the phenyl group is optionally substituted with NR¹⁰R¹⁰Alkoxy, morpholinyl, halogen or-SO₂Morpholinyl substitution;

R¹⁰independently at each occurrence is H, alkyl, phenyl optionally substituted with hydroxy or alkoxy, or phenylalkyl wherein the phenyl group is optionally substituted with halo;

R¹¹is a compound of formula (I) in the formula (H),

alkyl optionally substituted with one or two groups independently selected from phenyl, pyridyl and cycloalkyl,

phenylalkyl, wherein the phenyl radical is optionally substituted by halogen, alkoxy or haloalkyl,

phenyl optionally substituted by benzyloxy, furyl, cycloalkylalkyl, thienyl, -CO ₂Alkyl, -CO₂Alkylphenyl or-CO alkyl;

R¹²is alkyl, heteroalkyl having 1, 2 or 3 heteroatoms independently selected from O, N and S, or phenyl, wherein said heteroalkyl is optionally substituted with one or two groups independently selected from: alkyl, alkoxy, alkoxycarbonyl, haloalkoxy, halogen, haloalkyl, CN, NO₂Alkyl carbonyl amino groupOxazolyl (oxazolyl), -OCH₂O- (methylenedioxy group attached to adjacent positions of phenyl ring) and-OCH₂CH₂O- (ethylenedioxy group attached to adjacent positions of the phenyl ring),

R¹³is a heteroaromatic or non-aromatic heterocyclic 5-or 6-membered group having 1, 2 or 3 heteroatoms independently selected from O, N and S, said group being optionally substituted with one or two groups independently selected from alkyl, pyridyl, alkoxycarbonyl, oxazolyl and oxazolyl substituted with alkyl or alkoxycarbonyl;

R¹⁴is a heteroaromatic or non-aromatic heterocyclic 5-or 6-membered monocyclic or heteroaromatic 9-or 10-membered bicyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, said monocyclic or bicyclic group optionally being independently selected from alkyl, haloalkyl, -NR¹⁰R¹⁰Morpholinyl and 2-pyrrolidone;

R¹⁵Is hydroxy, alkoxy, haloalkoxy, alkoxyalkoxy, phenylalkoxy, pyranyloxy, NR¹⁰R¹⁰Morpholinyl, cycloalkyl, -CONR¹⁰R¹⁰、-COOR¹⁰、-CH₂F、-CHF₂、 -CF₃Or a group of-CN,

R¹⁶is alkyl optionally substituted by phenyl or pyridyl,

R¹⁷is a compound of formula (I) in the formula (H),

an alkyl group, a carboxyl group,

a halogenated alkyl group,

an alkoxyalkyl group, a substituted alkoxy group,

a cycloalkyl group,

a heteroaromatic 5-or 6-membered group having 1, 2 or 3 heteroatoms independently selected from O, N and S, said group being optionally substituted by alkyl or alkoxy,

a morpholinoalkyl group having a nitrogen atom in the alkyl group,

a cycloalkylalkyl group,

an N-benzylpyrrolidinyl group, a substituted benzyl group,

phenyl optionally substituted by alkyl, alkoxy, haloalkyl, -NR¹⁰R¹⁰Or halogen is takenInstead of the first generation,

phenylalkyl, wherein the phenyl radical is optionally substituted by alkyl, haloalkyl or halogen, or

R¹⁷And R¹⁰Together form a cycloalkyl ring optionally substituted with acetamido,

R¹⁸is alkyl, halogenated alkyl, phenyl,

Optionally substituted by-NR¹⁰R¹⁰Substituted morpholinyl or pyrrolidinyl;

R¹⁹is H, alkyl, phenylalkyl, phenyl substituted by alkoxy, or is alkylene-SO₂-alkyl or

R²⁰Is phenyl, optionally substituted with alkyl, phenyl or phenyl substituted with alkyl or hydroxyalkyl;

R²¹is NR¹⁰R¹⁰Alkyl or phenyl optionally substituted with halogen;

R²²Is H, alkyl or phenyl;

R²³is phenyl or phenyl substituted by alkyl, optionally substituted by piperazinyl or alkyl-substituted piperazinyl;

R²⁴is alkyl, thienyl substituted by alkyl or NR²⁵R²⁵；

R²⁵Independently at each occurrence, H or alkyl, or two R²⁵The group together with the nitrogen atom to which it is attached forms an alkylene or oxaalkylene (oxaalkylene) group;

R²⁶at each occurrence is independently:

H，

an alkyl group, a carboxyl group,

a phenylalkyl group,

an alkyl-carbonyl group, a carboxyl group,

an alkylsulfonyl group, or

A heteroaromatic 5-or 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, said group being optionally substituted by alkyl or halogen,

phenyl optionally substituted with: NR (nitrogen to noise ratio)¹⁰R¹⁰Halogen, alkoxy, a non-aromatic heterocyclic 5-or 6-membered monocyclic group having 1, 2 or 3 heteroatoms selected from O, N and S, alkylsulfonyl and heteroalkylsulfonyl;

R²⁷is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with one or two groups independently selected from halogen, alkoxy, haloalkoxy, alkyl and haloalkyl, phenylalkyl,

thienyl, optionally substituted with one or two groups independently selected from: halogen, alkyl, haloalkyl and aromatic heterocyclic 5-or 6-membered monocyclic radicals having 1, 2 or 3 heteroatoms independently selected from O, N and S, or

NR¹⁰R¹⁰，

R²⁸Is phenyl, quinolyl, alkylsulfonyl, or substituted by halogen, alkyl, NR¹⁰R¹⁰Morpholinyl or morpholinosulfonyl substituted phenyl.

Drawings

FIG. 1 is a Kaplan-Meier plot of survival rate of compounds of the invention compared to that of the compounds of the invention.

Fig. 2 is a graph showing the percentage of BrdU positive cells after co-incubation of compounds according to examples 1 and 2 in cultured primary mouse hepatocytes.

Detailed Description

In one embodiment, R⁵Comprises the following steps:

H，

the halogen(s) are selected from the group consisting of,

alkyl optionally substituted with 1 or 2 groups independently selected from: alkoxy, NR¹⁰R¹⁰、 -COOR¹⁰And an oxadiazolyl group, and a oxadiazole group,

an alkoxy group,

an alkenyl group, which is a radical of an alkenyl group,

an alkynyl group,

phenyl optionally substituted with 1, 2 or 3 groups independently selected from: alkyl, halogen, haloalkyl, hydroxyalkyl, alkylsulfonyl-NR¹⁰-、NR¹⁰R¹⁰Alkoxy, benzyloxy, haloalkoxy, NO₂、-COOR¹⁰、-CONR¹⁰R¹⁰CN, alkylcarbonyl-NR¹⁰-, alkenyl and carboxyl-substituted alkenyl,

NR¹⁰R²⁸，

a heteroaromatic or non-aromatic heterocyclic 5-or 6-membered monocyclic or heteroaromatic 9-or 10-membered bicyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, said monocyclic or bicyclic group being optionally substituted with 1 or 2 groups independently selected from: alkyl, alkoxy, morpholinyl, piperazinyl, oxadiazolyl and phenylcarbonyl optionally substituted with alkyl, halo and alkoxy.

In another embodiment, R⁵Comprises the following steps:

the halogen(s) are selected from the group consisting of,

phenyl optionally substituted with 1, 2 or 3 groups independently selected from: alkyl, halogen, haloalkyl, alkylsulfonyl-NR¹⁰-、NO₂、-COOR¹⁰and-CONR¹⁰R¹⁰Or is or

A heteroaromatic 5-or 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, said group being optionally substituted with 1 or 2 groups independently selected from: alkyl, alkoxy, morpholinyl, piperazinyl, oxadiazolyl and phenylcarbonyl wherein the phenyl is optionally substituted with alkyl, halo or alkoxy.

In yet another embodiment, R⁵Is a halogen, a heteroaromatic 5-or 6-membered monocyclic group having 1, 2 or 3 heteroatoms independently selected from O, N and S, or a phenyl group optionally substituted with 1 or 2 groups independently selected from: halogen, alkyl, NR¹⁰R¹⁰、-OCH₂O-、-OCH₂CH₂O-and alkoxy groups.

In yet another embodiment, R⁵Is phenyl substituted with 1, 2 or 3 groups independently selected from: alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkylthio, NH₂Alkoxy, haloalkoxy, -OCH₂O- (methylenedioxy group attached to adjacent positions of phenyl ring), -OCH ₂CH₂O- (ethylenedioxy group bonded to adjacent position of phenyl ring) and CN, or R⁵Is naphthyl, thienyl, furyl or quinolyl, which is optionally substituted by alkyl, halogen or alkoxy.

In yet another embodiment, R¹、R²、R⁴And R⁶Independently of one another, H or alkyl, in particular H.

In yet another embodiment, R¹⁰Independently at each occurrence is H, alkyl or phenylalkyl, wherein the phenyl group is optionally substituted with halogen, in particular R¹⁰Independently at each occurrence is H or alkyl.

In yet another embodiment, a is-CO-, -CO-, -CH (oh) -or-CH ═ CH-.

In yet another embodiment, A is-CO-.

In yet another embodiment, Q is a substituted phenyl group as defined above.

In yet another embodiment, the invention relates to inhibitors of MKK4 and pharmaceutically acceptable salts, solvates, and optical isomers thereof, wherein the MKK4 inhibitor has formula I, wherein R is¹To R⁶、R¹⁰A and Q are as defined above in any combination.

In yet another embodiment, the invention relates to inhibitors of MKK4 and pharmaceutically acceptable salts, solvates, and optical isomers thereof, wherein the inhibitors of MKK4 have formula Ia

Wherein

R¹Is H or alkyl;

R²Is H or alkyl;

R⁴is H or alkyl;

R⁶is H or alkyl;

R¹⁰is H, alkyl or phenylalkyl;

R¹²is H, alkyl or phenylalkyl;

R^wis-NR¹⁰SO₂R¹²or-N ═ S (═ O) R¹⁰NR¹⁰R¹⁰；

R^xIs H, halogen or alkyl;

R^yis H, halogen or alkyl;

R⁵is phenyl substituted with 1, 2 or 3 groups independently selected from: alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkylthio, NH₂Alkoxy, haloalkoxy, -OCH₂O- (methylenedioxy attached to adjacent positions of the phenyl ring), -OCH₂CH₂O- (ethylenedioxy group attached to adjacent positions of the phenyl ring) and CN, or

R⁵Is naphthyl, thienyl, furyl or quinolyl, which is optionally substituted by alkyl, halogen or alkoxy.

In embodiments of formula Ia, R^xOr R^yOne of which is alkyl or halogen, R^xAnd R^yIs H, halogen or alkyl, in particular alkyl or halogen. Halogen is preferably F or Cl. In particular, R^xAnd R^yAre both fluorine, most preferably in the ortho position to the carbonyl group. In another embodiment, R^wAt the 3-position relative to the carbonyl group. Preferably, R^wis-NR¹⁰SO₂R¹²。

In another embodiment of formula Ia, R¹⁰Is H or alkyl.

In another embodiment of formula Ia, R¹²Is an alkyl group.

Furthermore, the present invention relates to compounds of formula (Ia) wherein the variables are as defined above.

In one embodiment, formula (Ia) and pharmaceutically acceptable salts, solvates, and optical isomers thereof excludes the following compounds:

in one embodiment, the MKK4 inhibitors of formula (I) and (Ia) and compounds of formula (Ia) and their pharmaceutically acceptable salts, solvates, and optical isomers, inhibit protein kinase MKK4 selectively to protein kinases JNK1 and MKK 7.

Furthermore, the invention relates to the use of said compounds for promoting liver regeneration or for reducing or preventing hepatocyte death while increasing hepatocyte proliferation.

In one embodiment, the present invention relates to MKK4 inhibitors and pharmaceutically acceptable salts, solvates, and optical isomers thereof selected from the group consisting of:

propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl ] -2, 4-difluoro-phenyl } amide;

propane-1-sulfonic acid [3- (5-chloro-1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluoro-phenyl } amide;

propane-1-sulfonic acid [3- (5-bromo-1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluoro-phenyl } amide;

propane-1-sulfonic acid [3- (1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluoro-phenyl } amide; and

propane-1-sulfonic acid [3- (5-chloro-1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluoro-phenyl } -N-methylamide.

The invention also includes pharmaceutically acceptable salts of the above compounds. Said pharmaceutically acceptable salts are in particular acid or base addition salts employing pharmaceutically acceptable acids or bases. Examples of suitable pharmaceutically acceptable organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, sulfamic acid, C₁-C₄Alkyl sulfonic acids, such as methanesulfonic acid, cycloaliphatic sulfonic acids, such as S- (+) -10-camphorsulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, dicarboxylic and tricarboxylic acids having 2 to 10 carbon atomsAnd hydroxycarboxylic acids such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid. Other acids which can be used are described, for example, in Fortschritte der Arzneimitelforkung [ Advances in drug research ]],Volume 10,pages 224ff.,

Verlag, Basel and Stuttgart, 1966. Examples of suitable pharmaceutically acceptable organic and inorganic bases are alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide or magnesium hydroxide, ammonium hydroxide, organic nitrogen bases such as dimethylamine, trimethylamine, ethanolamine, diethanolamine, triethanolamine, choline, 2-amino-2-hydroxymethylpropane-1, 3-diol, meglumine, procaine and the like, L-arginine, L-lysine, ethylenediamine or hydroxyethylpyrrolidine.

The invention also includes any tautomeric, crystalline and polymorphic forms of the compounds and salts of the invention and mixtures thereof.

The invention also includes solvates, such as hydrates.

The compounds of the invention may contain one or more chiral centers and exist in different optically active forms, such as enantiomers and diastereomers.

As used herein, the term "prodrug" refers to an agent that is converted in vivo to the parent drug by some physiochemical process. One non-limiting example of a prodrug is a compound of the invention as an ester.

Prodrugs have many useful properties. For example, a prodrug may be more water soluble than the final drug, thereby facilitating intravenous administration of the drug. Prodrugs may also have a higher level of oral bioavailability than the final drug. After administration, the prodrug is cleaved enzymatically or chemically to deliver the final drug in the blood or tissue. Exemplary prodrugs include, but are not limited to: a compound having a carboxylic acid substituent wherein the free hydrogen is replaced by: (C)₁-C₄) Alkyl radical (C)₁-C₁₂) Alkanoyloxy-methyl group, (C)₄-C₉)1- (alkanoyloxy) ethyl, 1-methyl-1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyl-oxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) -ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthaloyl (3-phthaloyl), 4-crotonyl-lactone (4-crotono-lactonyl), γ -butyrolactone-4-yl, di-N, n- (C) ₁-C₂) Alkylamino (C)₂-C₃) Alkyl (e.g.. beta. -dimethylaminoethyl), carbamoyl- (C)₁-C₂) Alkyl, N, N-di (C)₁-C₂) -alkylcarbamoyl- (C)₁-C₂) Alkyl and piperidinyl-, pyrrolidinyl-or morpholinyl (C)₂-C₃) An alkyl group. Other exemplary prodrugs release alcohols of formula (I) wherein the free hydrogen of the hydroxy substituent (e.g., the R group contains a hydroxy group) is replaced by: (C)₁-C₆) Alkanoyloxy-methyl, 1- ((C)₁-C₆) Alkanoyloxy) -ethyl, 1-methyl-1- ((C)₁-C₆) Alkanoyloxy) ethyl group, (C)₁-C₁₂) Alkoxy-carbonyl oxy-methyl, N- (C)₁-C₆) -alkoxy-carbonylaminomethyl, succinyl, (C)₁-C₆) Alkanoyl, alpha-amino (C)₁-C₄) Alkanoyl, arylacyl (arylacyl) and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl wherein the alpha-aminoacyl moiety is independently any naturally occurring L-amino acid found in a protein, P (O), (OH)₂，-P(O)(O(C₁-C₆) Alkyl radical)₂Or a glycosyl (a radical generated by the separation of the hydroxyl group of the hemiacetal of a carbohydrate).

By the expression MKK4 inhibitor is meant that after administration, the kinase activity of MKK4 is inhibited, IC₅₀<10. mu. mol/l, preferably<1. mu. mol/l, in particular<0.5. mu. mol/l. As used herein, the expression "selectively inhibiting the protein kinase MKK4 but not the protein kinases JNK1 and MKK 7" refers to the use of KINOMEscan ^TMAt the time of measurement, MThe ratio of KK7 inhibitory activity to MKK4 inhibitory activity or the ratio of JNK1 inhibitory activity to MKK4 inhibitory activity (expressed as a percentage of control or Kd) ≥ 10.

The expression "promoting liver regeneration or reducing or preventing hepatocyte death" as used herein means that the relative number of proliferating hepatocytes is increased by at least 30%, preferably by at least 50% compared to the number of proliferating cells at the start of the treatment. In particular, the expression means an increase of > 100% compared to the number of proliferating cells at the start of the treatment. In this case, the experimental determination and quantification will be carried out using standard methods, for example, the quantification of the protein Ki67, which is strictly associated with cell proliferation. For quantification of proliferating hepatocytes in tissue slides, several standard immunohistochemical methods can be used, using a primary anti-Ki 67 antibody followed by visualization of anti-Ki 67 binding by using, for example, horseradish peroxidase conjugated secondary antibodies. The amount of peroxidase activity visualized by enzymatic conversion of the chromogenic substrate correlates with the amount of Ki67 protein and the number of proliferating cells.

In the following experiments, hepatocyte proliferation was quantified by Ki67 staining using a primary polyclonal rabbit anti-Ki 67 antibody from Abcam (product number ab15580, Abcam, Cambridge, USA) and the fluorophore tetramethylrhodamine containing a secondary goat polyclonal antibody from Invitrogen (product number 16101, Invitrogen/ThermoFisher). Based on data obtained from several preclinical mouse models, it was found that in chronic CCl ₄shRNA (small hairpin RNA) -mediated inhibition of MKK4 in a mouse model of liver injury mediated by carbon tetrachloride increased hepatocyte proliferation from 13% to 27% (compared to control shRNA) and was associated with decreased liver injury (transaminase) and decreased liver fibrosis. The relative increase in proliferating cells was 108% as defined in the previous section. In the alcohol-induced steatohepatitis (ASH) model, shRNA-mediated silencing of MKK4 resulted in a hepatocyte proliferation rate of 4% compared to 2% (relative increase: 100%) when using a control shRNA. Replication of hepatocyte proliferation is associated with decreased steatosis (fatty deposits) and decreased liver damage as measured by transaminase. Also, in the model of partial hepatectomy (two thirds of the liver is surgically removed)48 hours), shRNA-mediated silencing of MKK4 increased hepatocyte proliferation from 16% (control shRNA) to 33% (relative increase: 106%). Also, increased hepatocyte proliferation is associated with improved liver regeneration and faster recovery of liver mass.

The organic moieties mentioned in the above definitions of the variable, such as the term halogen, are each listed collective term for each member of the group. Prefix C_n-C_mIn each case representing the possible number of carbon atoms in the radical.

The term halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine or chlorine.

Alkyl is straight or branched chain alkyl, preferably C₁-C₆Alkyl, i.e. alkyl having 1 to 6 carbon atoms, more preferably C₁-C₄-an alkyl group. Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

The definition of alkyl applies equally to any group that includes alkyl.

Haloalkyl is a haloalkyl as defined above wherein at least one, e.g. 1,2, 3, 4 or all hydrogen atoms are replaced by 1,2, 3, 4 or a corresponding number of identical or different halogen atoms, such as trifluoromethyl, chloromethyl, bromomethyl, difluoromethyl, fluoromethyl, difluoroethyl and the like. Specific examples include fluorinated C as defined ₁-C₄Alkyl, such as trifluoromethyl, difluoromethyl, fluoromethyl or difluoroethyl.

Cycloalkyl is an alicyclic radical, preferably C₃-C₈Cycloalkyl, i.e. having 3 to 8 carbonsCycloalkyl of an atom. In particular, 3 to 6 carbon atoms form a cyclic structure, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclic structure may be unsubstituted or may carry 1, 2, 3 or 4C₁-C₄Alkyl groups, preferably with one or more methyl radicals.

Carbonyl is > C ═ O.

Aminocarbonyl is NH₂C(O)-。

Alkenyl is a monounsaturated hydrocarbyl radical, preferably C₂-C₆Alkenyl, i.e. alkenyl having 2, 3, 4, 5 or 6 carbon atoms, such as vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl (2-methylprop-2-en-1-yl), and the like. C₃-C₅Alkenyl is in particular allyl, 1-methylprop-2-en-1-yl, 2-buten-1-yl, 3-buten-1-yl, methallyl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl or 2-ethylprop-2-en-1-yl, 2-hexen-1-yl.

Alkynyl is a monounsaturated hydrocarbyl radical, preferably C₂-C₆Alkynyl, i.e. alkynyl having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propyn-1-yl, 1-propyn-1-yl, 2-propyn-2-yl and the like. C ₃-C₅Alkynyl is in particular 2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl.

Alkylene is straight-chain or branched alkylene, preferably C₁-C₅Alkylene, i.e. alkylene having 1 to 5 carbon atoms. Examples include methylene, ethylene and 1-methylethylene. Another example is propylene. Another example is butylene. The definition of alkylene applies equally to any group comprising alkylene.

Heteroalkylene (heteroalkyllene) is a linear or branched alkyl group having 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur. Examples of heteroalkylene are alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl or alkylsulfanyl. Any alkyl or alkylene group is as defined above. Alkoxyalkyl groups are preferred.

Alkenylene is a straight-chain or branched alkenylene, which is preferably C_2-C₄Alkenylene, i.e. alkenylene having 2 to 4 carbon atoms. Examples include ethenyl and propenyl.

Alkynylene (alkinyl) is a straight or branched alkynylene group, preferably C_2-C₄Alkynylene, i.e. alkynylene having 2 to 4 carbon atoms. Examples include propynyl.

Aryl (or aromatic group) is a 6 to 12-membered, especially 6 to 10-membered, aromatic cyclic radical, which may be a monocyclic aromatic ring, such as phenyl, etc., or a fused polycyclic aromatic ring, which comprises a first monocyclic aromatic ring and one or more saturated, partially unsaturated or aromatic carbocyclic rings, such as naphthyl, indenyl, tetrahydronaphthyl, indanyl (indanyl).

The heteroaromatic (or heteroaryl) group is a 5-or 6-membered monocyclic or 9-or 10-membered bicyclic aromatic group having 1,2 or 3 heteroatoms selected from O, N and S. The heteroaryl or heteroaromatic group may be bonded to an adjacent group through a carbon atom (C-bond) or through a nitrogen heteroatom (N-bond). The heterocyclic radical may be bonded via a carbon atom (C-bond) or a nitrogen atom (N-bond). Preferred heteroaromatic radicals comprise 1 nitrogen atom as ring member atom and optionally 1 or 2 further heteroatoms as ring members, which heteroatoms are independently from each other selected from O, S and N. Examples are:

c-bonded 5-membered heteroaromatic ring:

2-furyl, 3-furyl, 5-furyl, 2-thienyl, 3-thienyl, 5-thienyl, pyrrol-2-yl, pyrrol-3-yl, pyrrol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1,2, 3-oxadiazol-imidazol-4-yl, 1,2, 3-oxadiazol-5-yl, 1,2, 4-oxadiazol-3-yl, 1,2, 4-oxadiazol-5-yl, 1,3, 4-oxadiazol-2-yl, 1,2, 3-thiadiazol-4-yl, 1,2, 3-thiadiazol-5-yl, 1,2, 4-thiadiazol-3-yl, 1,2, 4-thiadiazol-5-yl, 1,3, 4-thiadiazol-2-yl, 1,2, 3-triazol-4-yl, 1,2, 4-triazol-3-yl, tetrazol-5-yl;

A C-bonded 6-membered heteroaromatic ring:

pyridin-2-yl, pyridin-3-yl (3-pyridyl), pyridin-4-yl (4-pyridyl), pyridin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-6-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-5-yl, 1,3, 5-triazin-2-yl, 1,2, 4-triazin-3-yl, 1,2, 4-triazin-5-yl, 1,2, 4-triazin-6-yl, 1,2,4, 5-tetrazin-3-yl;

an N-bonded 5-membered heteroaromatic ring:

pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2, 3-triazol-1-yl, 1,2, 4-triazol-1-yl.

Bicyclic heteroaromatic groups include one of the 5-or 6-membered heteroaromatic rings and additionally a fused (anellated), saturated or unsaturated or aromatic carbocyclic ring, for example a benzene, cyclohexane, cyclohexene or cyclohexadiene ring. Examples are quinolinyl, isoquinolinyl, indolyl, indolizinyl, isoindolyl, 4-, 5-, 6-or 7-azaindole, indazolyl, benzofuranyl, benzothienyl, benzo [ b ] thiazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, imidazo [ b ] thiazole, thieno [ b ] pyridyl, imidazo [ a ] pyridyl, pyrazolo [ a ] pyridyl and pyrrolo [ d ] pyrimidinyl (pyrimide). Examples of 5-or 6-membered heteroaromatic compounds comprising a fused cycloalkenyl ring include indolinyl, dihydroindolizinyl, dihydroisoindolyl, dihydroquinolinyl, dihydroisoquinolinyl, dihydrobenzofuranyl, chromenyl (chromenyl), chromanyl (chromanyl), dihydropyrrolo [ a ] imidazolyl and tetrahydrobenzothiazolyl.

The non-aromatic 5-or 6-membered group (heterocyclic group) may be saturated or partially unsaturated and comprise 1,2 or 3 heteroatoms selected from O, N and S. The heterocyclic group may be bonded via a carbon atom (C-bond) or a nitrogen atom (N-bond). Preferred heterocyclic groups comprise 1 nitrogen atom as ring member atom and optionally 1 or 2 further heteroatoms as ring members, which heteroatoms are independently from each other selected from O, S and N. Examples are:

c-bonded 5-membered saturated rings, e.g.

Tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydropyrroln-2-yl, tetrahydropyrroln-3-yl, tetrahydropyrazol-3-yl, tetrahydro-pyrazol-4-yl, tetrahydroisooxazol-3-yl, tetrahydroisooxazol-4-yl, tetrahydroisooxazol-5-yl, 1,2-oxathiolan-3-yl (1,2-oxathiolan-3-yl), 1, 2-oxathiolan-4-yl, 1, 2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl, tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl, 1, 2-dithiolan-3-yl, 1, 2-dithiolan-4-yl, tetrahydroimidazol-2-yl, tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl, tetrahydrooxazol-4-yl, tetrahydrooxazol-5-yl, tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl, tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl (1,3-dioxolan-2-yl), 1, 3-dioxolan-4-yl, 1, 3-oxathiolan-2-yl, 1, 3-oxathiolan-4-yl, 1, 3-oxathiolan-5-yl, 1, 3-dithiolan-2-yl, 1, 3-dithiolan-4-yl, 1,3, 2-dioxathiolan-4-yl;

C-bonded 6-membered saturated rings, e.g.

Tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, 1, 3-dioxan-2-yl, 1, 3-dioxan-4-yl, 1, 3-dioxan-5-yl, 1, 4-dioxan-2-yl, 1, 3-dithian-4-yl, 1, 3-dithian-5-yl, 1, 4-dithian-2-yl, 1,3-oxathian-2-yl (1,3-oxathian-2-yl), 1, 3-oxathian-4-yl, 1, 3-oxathian-5-yl, 1, 3-oxathian-6-yl, 1, 4-oxathian-2-yl, 1, 4-oxathian-3-yl, 1, 2-dithian-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, hexahydropyrazin-2-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, tetrahydro-1, 3-oxazin-2-yl, tetrahydro-1, 3-oxazin-4-yl, tetrahydro-1, 3-oxazin-5-yl, tetrahydro-1, 3-oxazin-6-yl, tetrahydro-1, 3-thiazin-2-yl, tetrahydro-1, 3-thiazin-4-yl, tetrahydro-1, 3-thiazin-5-yl, tetrahydro-1, 3-thiazin-6-yl, tetrahydro-1, 4-thiazin-2-yl, tetrahydro-1, 4-thiazin-3-yl, tetrahydro-1, 4-oxazin-2-yl, tetrahydro-1, 4-oxazin-3-yl, tetrahydro-1, 2-oxazin-3-yl, tetrahydro-1, 2-oxazin-4-yl, tetrahydro-1, 2-oxazin-5-yl, tetrahydro-1, 2-oxazin-6-yl;

N-bonded 5-membered saturated rings, e.g.

Pyrrolidin-1-yl (pyrrolidin-1-yl), tetrahydropyrazol-1-yl, tetrahydroisooxazol-2-yl, tetrahydroisothiazol-2-yl, tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl, thiazolidin-3-yl;

n-bonded 6-membered saturated rings, e.g.

Piperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl (piperazin-1-yl), hexahydro-pyridazin-1-yl, tetrahydro-1, 3-oxazin-3-yl, tetrahydro-1, 3-thiazin-3-yl, tetrahydro-1, 4-thiazin-4-yl, tetrahydro-1, 4-oxazin-4-yl (morpholin-1-yl), tetrahydro-1, 2-oxazin-2-yl;

c-bonded 5-membered partially unsaturated rings, e.g.

2, 3-dihydrofuran-2-yl, 2, 3-dihydrofuran-3-yl, 2, 5-dihydrofuran-2-yl, 2, 5-dihydrofuran-3-yl, 4, 5-dihydrofuran-2-yl, 4, 5-dihydrofuran-3-yl, 2, 3-dihydro-thiophen-2-yl, 2, 3-dihydrothiophen-3-yl, 2, 5-dihydrothiophen-2-yl, 2, 5-dihydrothiophen-3-yl, 4, 5-dihydrothiophen-2-yl, 4, 5-dihydrothiophen-3-yl, 2, 3-dihydro-1H-pyrrol-2-yl, 2, 3-dihydro-1H-pyrrol-3-yl, 2, 5-dihydro-1H-pyrrol-2-yl, 2, 5-dihydro-1H-pyrrol-3-yl, 4, 5-dihydro-1H-pyrrol-2-yl, 4, 5-dihydro-1H-pyrrol-3-yl, 3, 4-dihydro-2H-pyrrol-2-yl, 3, 4-dihydro-2H-pyrrol-3-yl, 3, 4-dihydro-5H-pyrrol-2-yl, 3, 4-dihydro-5H-pyrrol-3-yl, 4, 5-dihydro-1H-pyrazol-3-yl, 4, 5-dihydro-1H-pyrazol-4-yl, 4, 5-dihydro-1H-pyrazol-5-yl, 2, 5-dihydro-1H-pyrazol-3-yl, 2, 5-dihydro-1H-pyrazol-4-yl, 2, 5-dihydro-1H-pyrazol-5-yl, 4, 5-dihydroisoxazol-3-yl, 4, 5-dihydroisoxazol-4-yl, 4, 5-dihydroisoxazol-5-yl, 2, 5-dihydro-isoxazol-3-yl, 2, 5-dihydroisoxazol-4-yl, 2, 5-dihydroisoxazol-5-yl, 2, 3-dihydroisoxazol-3-yl, 2, 3-dihydroisoxazol-4-yl, 2, 3-dihydroisoxazol-5-yl, 4, 5-dihydroisothiazol-3-yl, 4, 5-dihydroisothiazol-4-yl, 4, 5-dihydroisothiazol-5-yl, 2, 5-dihydroisothiazol-3-yl, 2, 5-dihydroisothiazol-4-yl, 2, 5-dihydroisothiazol-5-yl, 2, 3-dihydroisothiazol-3-yl, 2, 3-dihydroisothiazol-4-yl, 2, 3-dihydroisothiazol-5-yl, 4, 5-dihydro-1H-imidazol-2-yl, 4, 5-dihydro-1H-imidazol-4-yl, 4, 5-dihydro-1H-imidazol-5-yl, 2, 5-dihydro-1H-imidazol-2-yl, 2, 5-dihydro-1H-imidazol-4-yl, 2, 5-dihydro-1H-imidazol-5-yl, 2, 3-dihydro-1H-imidazol-2-yl, 2, 3-dihydro-1H-imidazol-4-yl, 4, 5-dihydro-oxazol-2-yl, 4, 5-dihydrooxazol-4-yl, 4, 5-dihydrooxazol-5-yl, 2, 5-dihydrooxazol-2-yl, 2, 5-dihydrooxazol-4-yl, 2, 5-dihydrooxazol-5-yl, 2, 3-dihydrooxazol-2-yl, 2, 3-dihydrooxazol-4-yl, 2, 3-dihydrooxazol-5-yl, 4, 5-dihydrothiazol-2-yl, 4, 5-dihydro-thiazol-4-yl, 4, 5-dihydrothiazol-5-yl, 2, 5-dihydrothiazol-2-yl, 2, 5-dihydro-thiazol-4-yl, 2, 5-dihydrothiazol-5-yl, 2, 3-dihydrothiazol-2-yl, 2, 3-dihydrothiazol-4-yl, 2, 3-dihydrothiazol-5-yl, 1, 3-dioxol (dioxol) -2-yl, 1, 3-dioxol-4-yl, 1, 3-dithiol-2-yl, 1, 3-dithiol-4-yl, 1, 3-oxathiolan (oxathiol) -2-yl, 1, 3-oxathiolan-4-yl, 1, 3-oxathiapent-5-yl;

C-bonded 6-membered partially unsaturated rings, e.g.

2H-3, 4-dihydropyran-6-yl, 2H-3, 4-dihydropyran-5-yl, 2H-3, 4-dihydropyran-4-yl, 2H-3, 4-dihydropyran-3-yl, 2H-3, 4-dihydropyran-2-yl, 2H-3, 4-dihydrothiopyran-6-yl, 2H-3, 4-dihydrothiopyran-5-yl, 2H-3, 4-dihydrothiopyran-4-yl, 2H-3, 4-dihydrothiopyran-3-yl, 2H-3, 4-dihydrothiopyran-2-yl, 1,2,3, 4-tetrahydropyridin-6-yl, 1,2,3, 4-tetrahydropyridin-5-yl, 1,2,3, 4-tetrahydropyridin-4-yl, 1,2,3, 4-tetrahydropyridin-3-yl, 1,2,3, 4-tetrahydropyridin-2-yl, 2H-5, 6-dihydropyran-3-yl, 2H-5, 6-dihydropyran-4-yl, 2H-5, 6-dihydropyran-5-yl, 2H-5, 6-dihydropyran-6-yl, 2H-5, 6-dihydrothiopyran-2-yl, 2H-5, 6-dihydrothiopyran-3-yl, 2H-5, 6-thiochroman-4-yl, 2H-5, 6-thiochroman-5-yl, 2H-5, 6-thiochroman-6-yl, 1,2,5, 6-tetrahydropyridin-2-yl, 1,2,5, 6-tetrahydropyridin-3-yl, 1,2,5, 6-tetrahydropyridin-4-yl, 1,2,5, 6-tetrahydropyridin-5-yl, 1,2,5, 6-tetrahydropyridin-6-yl, 2,3,4, 5-tetrahydropyridin-2-yl, 2,3,4, 5-tetrahydropyridin-3-yl, 2,3,4, 5-tetrahydropyridin-4-yl, 2,3,4, 5-tetrahydropyridin-5-yl, 2,3,4, 5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl, 4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, 4H-thiopyran-4-yl, 1, 4-dihydropyridin-2-yl, 1, 4-dihydropyridin-3-yl, 1, 4-dihydropyridin-4-yl, 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl, 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran-6-yl, 1, 2-dihydropyridin-2-yl, 1, 2-dihydro-pyridin-3-yl, 1, 2-dihydropyridin-4-yl, 1, 2-dihydropyridin-5-yl, 1, 2-dihydro-pyridin-6-yl, 3, 4-dihydropyridin-2-yl, 3, 4-dihydropyridin-3-yl, 3, 4-dihydro-pyridin-4-yl, 3, 4-dihydropyridin-5-yl, 3, 4-dihydropyridin-6-yl, 2, 5-dihydropyridin-2-yl, 2, 5-dihydropyridin-3-yl, 2, 5-dihydropyridin-4-yl, 2, 5-dihydropyridin-5-yl, 2, 5-dihydropyridin-6-yl, 2, 3-dihydropyridin-2-yl, 2, 3-dihydropyridin-3-yl, 2, 3-dihydropyridin-4-yl, 2, 3-dihydropyridin-5-yl, 2, 3-dihydropyridin-6-yl, 2H-5, 6-dihydro-1, 2-oxazin-3-yl, 2H-5, 6-dihydro-1, 2-oxazin-4-yl, 2H-5, 6-dihydro-1, 2-oxazin-5-yl, 2H-5, 6-dihydro-1, 2-oxazin-6-yl, 2H-5, 6-dihydro-1, 2-thiazin-3-yl, 2H-5, 6-dihydro-1, 2-thiazin-4-yl, 2H-5, 6-dihydro-1, 2-thiazin-5-yl, 2H-5, 6-dihydro-1, 2-thiazin-6-yl, 4H-5, 6-dihydro-1, 2-oxazin-3-yl, 4H-5, 6-dihydro-1, 2-oxazin-4-yl, 4H-5, 6-dihydro-1, 2-oxazin-5-yl, 4H-5, 6-dihydro-1, 2-oxazin-6-yl, 4H-5, 6-dihydro-1, 2-thiazin-3-yl, 4H-5, 6-dihydro-1, 2-thiazin-4-yl, 4H-5, 6-dihydro-1, 2-thiazin-5-yl, 4H-5, 6-dihydro-1, 2-thiazin-6-yl, 2H-3, 6-dihydro-1, 2-oxazin-3-yl, 2H-3, 6-dihydro-1, 2-oxazin-4-yl, 2H-3, 6-dihydro-1, 2-oxazin-5-yl, 2H-3, 6-dihydro-1, 2-oxazin-6-yl, 2H-3, 6-dihydro-1, 2-thiazin-3-yl, 2H-3, 6-dihydro-1, 2-thiazin-4-yl, 2H-3, 6-dihydro-1, 2-thiazin-5-yl, 2H-3, 6-dihydro-1, 2-thiazin-6-yl, 2H-3, 4-dihydro-1, 2-oxazin-3-yl, 2H-3, 4-dihydro-1, 2-oxazin-4-yl, 2H-3, 4-dihydro-1, 2-oxazin-5-yl, 2H-3, 4-dihydro-1, 2-oxazin-6-yl, 2H-3, 4-dihydro-1, 2-thiazin-3-yl, 2H-3, 4-dihydro-1, 2-thiazin-4-yl, 2H-3, 4-dihydro-1, 2-thiazin-5-yl, 2H-3, 4-dihydro-1, 2-thiazin-6-yl, 2,3,4, 5-tetrahydropyridazin-3-yl, 2,3,4, 5-tetrahydropyridazin-4-yl, 2,3,4, 5-tetrahydropyridazin-5-yl, 2,3,4, 5-tetrahydropyridazin-6-yl, 3,4,5, 6-tetrahydropyridazin-3-yl, 3,4,5, 6-tetrahydropyridazin-4-yl, 1,2,5, 6-tetrahydropyridazin-3-yl, 1,2,5, 6-tetrahydropyridazin-4-yl, 1,2,5, 6-tetrahydropyridazin-5-yl, 1,2,5, 6-tetrahydropyridazin-6-yl, 1,2,3, 6-tetrahydro-pyridazin-3-yl, 1,2,3, 6-tetrahydropyridazin-4-yl, 4H-5, 6-dihydro-1, 3-oxazin-2-yl, 4H-5, 6-dihydro-1, 3-oxazin-4-yl, 4H-5, 6-dihydro-1, 3-oxazin-5-yl, 4H-5, 6-dihydro-1, 3-oxazin-6-yl, 4H-5, 6-dihydro-1, 3-thiazin-2-yl, 4H-5, 6-dihydro-1, 3-thiazin-4-yl, 4H-5, 6-dihydro-1, 3-thiazin-5-yl, 4H-5, 6-dihydro-1, 3-thiazin-6-yl, 3,4, 5-6-tetrahydropyrimidin-2-yl, 3,4,5, 6-tetrahydropyrimidin-4-yl, 3,4,5, 6-tetrahydropyrimidin-5-yl, 3,4,5, 6-tetrahydropyrimidin-6-yl, 1,2,3, 4-tetrahydropyrazin-2-yl, 1,2,3, 4-tetrahydropyrazin-5-yl, 1,2,3, 4-tetrahydro-pyrimidin-2-yl, 1,2,3, 4-tetrahydropyrimidin-4-yl, 1,2,3, 4-tetrahydropyrimidin-5-yl, 1,2,3, 4-tetrahydropyrimidin-6-yl, 2, 3-dihydro-1, 4-thiazin-2-yl, 2, 3-dihydro-1, 4-thiazin-3-yl, 2, 3-dihydro-1, 4-thiazin-5-yl, 2, 3-dihydro-1, 4-thiazin-6-yl, 2H-1, 3-oxazin-2-yl, 2H-1, 3-oxazin-4-yl, 2H-1, 3-oxazin-5-yl, 2H-1, 3-oxazin-6-yl, 2H-1, 3-thiazin-2-yl, 2H-1, 3-thiazin-4-yl, 2H-1, 3-thiazin-5-yl, 2H-1, 3-thiazin-6-yl, 4H-1, 3-oxazin-2-yl, 4H-1, 3-oxazin-4-yl, 4H-1, 3-oxazin-5-yl, 4H-1, 3-oxazin-6-yl, 4H-1, 3-thiazin-2-yl, 4H-1, 3-thiazin-4-yl, 4H-1, 3-thiazin-5-yl, 4H-1, 3-thiazin-6-yl, 6H-1, 3-oxazin-2-yl, 6H-1, 3-oxazin-4-yl, 6H-1, 3-oxazin-5-yl, 6H-1, 3-oxazin-6-yl, 6H-1, 3-thiazin-2-yl, 6H-1, 3-oxazin-4-yl, 6H-1, 3-oxazin-5-yl, 6H-1, 3-thiazin-6-yl, 2H-1, 4-oxazin-2-yl, 2H-1, 4-oxazin-3-yl, 2H-1, 4-oxazin-5-yl, 2H-1, 4-oxazin-6-yl, 2H-1, 4-thiazin-2-yl, 2H-1, 4-thiazin-3-yl, 2H-1, 4-thiazin-5-yl, 2H-1, 4-thiazin-6-yl, 4H-1, 4-oxazin-2-yl, 4H-1, 4-oxazin-3-yl, 4H-1, 4-thiazin-2-yl, 4H-1, 4-thiazin-3-yl, 1, 4-dihydropyridazin-4-yl, 1, 4-dihydropyridazin-5-yl, 1, 4-dihydropyridazin-6-yl, 1, 4-dihydropyrazin-2-yl, 1, 2-dihydropyrazin-3-yl, 1, 2-dihydropyrazin-5-yl, 1, 2-dihydropyrazin-6-yl, 1, 4-dihydropyrimidin-2-yl, 1, 4-dihydropyrimidin-4-yl, 1, 4-dihydropyrimidin-5-yl, 1, 4-dihydropyrimidin-6-yl, 3, 4-dihydropyrimidin-2-yl, 3, 4-dihydropyrimidin-4-yl, 3, 4-dihydropyrimidin-5-yl or 3, 4-dihydropyrimidin-6-yl;

N-bonded 5-membered partially unsaturated rings, e.g.

2, 3-dihydro-1H-pyrrol-1-yl, 2, 5-dihydro-1H-pyrrol-1-yl, 4, 5-dihydro-1H-pyrazol-1-yl, 2, 3-dihydro-1H-pyrazol-1-yl, 2, 5-dihydroisoxazol-2-yl, 2, 3-dihydroisoxazol-2-yl, 2, 5-dihydroisothiazol-2-yl, 2, 3-dihydroisoxazol-2-yl, 4, 5-dihydro-1H-imidazol-1-yl, 2, 5-dihydro-1H-imidazol-1-yl, 2, 3-dihydro-1H-imidazol-1-yl, 2, 3-dihydrooxazol-3-yl, 2, 3-dihydrothiazol-3-yl;

n-bonded 6-membered partially unsaturated rings, e.g.

1,2,3, 4-tetrahydropyridin-1-yl, 1,2,5, 6-tetrahydropyridin-1-yl, 1, 4-dihydro-pyridin-1-yl, 1, 2-dihydropyridin-1-yl, 2H-5, 6-dihydro-1, 2-oxazin-2-yl, 2H-5, 6-dihydro-1, 2-thiazin-2-yl, 2H-3, 6-dihydro-1, 2-oxazin-2-yl, 2H-3, 6-dihydro-1, 2-thiazin-2-yl, 2H-3, 4-dihydro-1, 2-oxazin-2-yl, 2H-3, 4-dihydro-1, 2-thiazin-2-yl, 2,3,4, 5-tetrahydropyridazin-2-yl, 1,2,5, 6-tetrahydropyridazin-1-yl, 1,2,5, 6-tetrahydropyridazin-2-yl, 1,2,3, 6-tetrahydropyridazin-1-yl, 3,4,5, 6-tetrahydropyrimidin-3-yl, 1,2,3, 4-tetrahydropyrazin-1-yl, 1,2,3, 4-tetrahydropyrimidin-3-yl, 2, 3-dihydro-1, 4-thiazin-4-yl, 2H-1, 2-oxazin-2-yl, 2H-1, 2-thiazin-2-yl, 4H-1, 4-oxazin-4-yl, 4H-1, 4-thiazin-4-yl, 1, 4-dihydropyridazin-1-yl, 1, 4-dihydropyrazin-1-yl, 1, 2-dihydro-pyrazin-1-yl, 1, 4-dihydropyrimidin-1-yl or 3, 4-dihydropyrimidin-3-yl.

Any group containing a heteroatom may contain 1, 2 or 3 heteroatoms which may be the same or different.

The compounds of the present invention, which are referred to herein and hereinafter as MKK4 inhibitors, as well as compounds of the present invention including pharmaceutically acceptable salts, prodrugs, biologically active metabolites, solvates and stereoisomers thereof, may be prepared as disclosed in WO 2007/002433, which is incorporated herein by reference in its entirety, or according to analogous procedures. Acid or base addition salts are prepared in a conventional manner by mixing the free base with the corresponding acid or by mixing the free acid with the desired base. Optionally, the reaction is carried out in a solution in an organic solvent, for example a lower alcohol such as methanol, ethanol or propanol, an ether such as methyl tert-butyl ether or diisopropyl ether, a ketone such as acetone or methyl ethyl ketone, or an ester such as ethyl acetate.

The compounds of the invention are useful for promoting liver regeneration or reducing or preventing hepatocyte death while increasing hepatocyte proliferation. Thus, the compounds are useful for treating, modulating, ameliorating or preventing diseases involving acute or chronic damage to the liver that may result from infection, injury, exposure to toxic compounds, abnormal accumulation of normal substances in the blood, autoimmune processes, genetic defects or unknown causes.

These liver diseases include all diseases in which increasing liver regeneration and reducing or preventing hepatocyte death may contribute to the potential therapeutic effect, i.e. partial or complete restoration of liver function. These diseases include:

acute and chronic or chronic plus acute (acute on chronic) liver diseases, such as acute and chronic viral hepatitis, e.g. hepatitis b, hepatitis c, hepatitis e, hepatitis caused by Epstein-Barr virus, cytomegalovirus, herpes simplex virus and other viruses, all types of autoimmune hepatitis, primary sclerosing hepatitis, alcoholic hepatitis;

metabolic liver diseases, such as metabolic syndrome, fatty liver diseases such as non-alcoholic fatty liver disease (NAFL), non-alcoholic steatohepatitis (NASH), Alcoholic Steatohepatitis (ASH), Wilson's disease (Morbus Wilson), hemochromatosis, α 1-antitrypsin deficiency, glycogen storage diseases (glycogenon storage diseases);

all types of cirrhosis, such as primary biliary cirrhosis, ethanol-toxic cirrhosis (ethyl toxin liver cirrhosis), cryptogenic cirrhosis;

acute (fulminant) or chronic liver failure, such as toxic liver failure, e.g. acetaminophen (paracetamol) -induced liver failure, alpha-amanitin-induced liver failure, e.g. drug-induced hepatotoxicity caused by antibiotics, non-steroidal anti-inflammatory drugs, anti-spasmodics, liver failure, acute liver failure induced by herbal supplements (kava, ephedra, scutellaria (skullcap), mint, etc.), liver and liver failure caused by vascular diseases such as Budd-Chiari syndrome, acute liver failure of unknown origin, chronic liver disease caused by right heart failure;

Galactosemia, cystic fibrosis, porphyria, hepatic ischemic perfusion injury, posthepatic steatosis, primary sclerosing cholangitis or hepatic encephalopathy.

To promote liver regeneration or reduce or prevent hepatocyte death, the compounds of the present invention are administered to a patient in need thereof in a therapeutically effective amount. The presence of liver disease can be detected by the presence of elevated enzyme levels in the blood. Blood levels of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) are known to be higher than the clinically acceptable normal range, indicating progressive (on-going) liver injury. Blood bilirubin levels or other liver enzymes may be used as a detection or diagnostic criteria. Blood ALT and AST levels are routinely monitored in patients with liver disease for measuring the progression of liver disease during treatment. Lowering elevated ALT and AST levels to within an acceptable normal range is considered clinical evidence reflecting a reduction in the severity of liver damage in the patient.

The compounds of the invention are generally administered in the form of pharmaceutical compositions comprising at least one compound according to the invention, optionally together with inert carriers (e.g. pharmaceutically acceptable adjuvants) and, where appropriate, other medicaments. These compositions may be administered, for example, orally, rectally, transdermally, subcutaneously, intraperitoneally, intravenously, intramuscularly, or intranasally.

Examples of suitable pharmaceutical compositions are solid pharmaceutical forms, such as powders, granules, tablets, in particular film tablets, dragees, sachets (sachets), cachets, sugar-coated tablets, capsules, such as hard and soft gelatin capsules, or suppositories, semisolid pharmaceutical forms, such as ointments, creams, hydrogels, pastes or plasters (plasters), and liquid pharmaceutical forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, such as lotions, injectable preparations and infusion preparations. In addition, liposomes or microspheres may also be used.

When preparing such compositions, the compounds according to the invention are optionally mixed or diluted with one or more carriers (excipients). The carrier (adjuvant) may be a solid, semi-solid or liquid material which acts as a (vehicle), carrier or medium for the active compound.

Suitable carriers (adjuvants) are listed in the specialist medical monograph. In addition, the formulation may contain pharmaceutically acceptable auxiliary substances, such as wetting agents; emulsifying and suspending agents; a preservative; an antioxidant; anti-irritants (antipirantants); a chelating agent; a coating auxiliary agent; an emulsion stabilizer; a film-forming agent; a gel forming agent; an odor masking agent; a taste-modifying agent; a resin; hydrocolloids (hydrocolloids); a solvent; a solubilizer; a neutralizing agent; a diffusion accelerator; a pigment; a quaternary ammonium compound; fatting agents (refatting agents) and superfatting agents (superfatting agents); raw materials for ointment, cream or oil; a silicone derivative; a dispersing aid; a stabilizer; a bactericide; a suppository base; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; a propellant; a desiccant; an opacifying agent; a thickener; a wax; plasticizers and white mineral oil. The formulations in this connection are based on expert knowledge, for example in Fiedler, H.P., Lexikon der Hilfsststoffe fur Pharmazie, Kosmetik und grenzede Gebiete [ Encyclopedia of auxiary substations for pharma, cosmetics and related fields (Encyclopedia of auxiliary substances in pharmacy, cosmetics and related fields) ],4^thedition (4 th edition), Aulendorf: ECV-edition-Cantor-Verlag, 1996.

The compounds of the present invention are also suitable in combination with other therapeutic agents. Thus, the invention also relates to a composition comprising a compound of the invention in combination with one or more other therapeutic agents, in particular for promoting liver regeneration or reducing or preventing hepatocyte death. The combination therapy of the present invention may be administered adjunctively. Adjuvant administration (adjuvant administration) refers to the sequential or superimposed administration of each component in the form of a separate pharmaceutical composition or device. Such therapeutic administration regimens of two or more therapeutic agents are generally known to those skilled in the art and are referred to herein as adjunctive therapeutic administration; it is also known as add-on therapy administration. Any and all treatment regimens in which a patient receives separate but sequential or superimposed therapeutic administration of a compound of the invention and at least one other therapeutic agent are within the scope of the invention. In one embodiment of adjunctive therapeutic administration as described herein, a patient is typically stabilized for a period of time for therapeutic administration of one or more components and then receives administration of another component. The combination therapies of the invention may also be administered simultaneously. By simultaneous administration is meant a treatment regimen wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device containing or containing both components, or as separate compositions or devices, each containing one of the components, administered simultaneously. Such combinations of individual components for simultaneous combination may be provided in the form of kits.

Suitable agents for use in combination with the compounds of the present invention include, for example:

ACC inhibitors such as TOFA (5- (tetradecyloxy) -2-furoic acid), GS 0976 and ACC inhibitors as disclosed in WO 2016/112305,

an angiotensin II receptor antagonist which is capable of inhibiting the growth of angiotensin II receptor,

angiotensin Converting Enzyme (ACE) inhibitors, such as enalapril (enalapril),

caspase inhibitors, such as emricasan (emricasan),

cathepsin B inhibitors, e.g., mixed cathepsin B/hepatitis C virus NS3 protease inhibitors, e.g., VBY-376,

CCR2 chemokine antagonists, for example mixed CCR2/CCR5 chemokine antagonists, such as cenicriviroc (cenicriviroc),

an antagonist of the CCR5 chemokine enzyme,

chloride channel stimulants, such as cobiprostone,

a cholesterol-solubilizing agent which is a compound selected from the group consisting of,

diacylglycerol O-acyltransferase 1(DGAT1) inhibitors, such as LCQ908,

dipeptidyl peptidase IV (DPPIV) inhibitors, such as linagliptin (linagliptin),

farnesoid X Receptor (FXR) agonists, e.g. INT-747 (obeticholic acid) or GS-9674

(PX-102)，

FXR/TGR5 dual agonists, such as INT-767,

galectin-3 inhibitors, such as GR-MD-02,

glucagon-like peptide 1(GLP1) agonists, such as liraglutide or exenatide,

A precursor of glutathione,

hepatitis C virus NS3 protease inhibitors, e.g., mixed cathepsin B/hepatitis C virus NS3 protease inhibitors such as VBY-376,

HMG CoA reductase inhibitors, for example statins, such as atorvastatin,

inhibitors of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD 1), such as R05093151,

an antagonist of IL-1 beta, or an antagonist of IL-1 beta,

IL-6 antagonists, e.g., mixed IL-6/IL-1 β/TNF α ligand inhibitors, such as BLX-1002,

IL-10 agonists, such as polyethylene glycol-ilointerleukin (peg-ilodeckin),

IL-17 antagonists, such as KD-025,

ileal sodium bile acid cotransporter inhibitors, such as SHP-626,

leptin analogs, such as metreleptin,

5-lipoxygenase inhibitors, for example mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitors such as tipelukast,

LPL gene stimulants, such as for example alisporene tipivovec,

lysyl oxidase homolog 2(LOXL2) inhibitors, e.g., anti-LOXL 2 antibodies, such as GS-6624,

PDE3 inhibitors, for example mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitors, such as tipelukast,

PDE4 inhibitors, for example ASP-9831 or mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitors such as tipelukast,

Phospholipase C (PLC) inhibitors, e.g., mixed 5-lipoxygenase/PDE 3/PDE4/PLC inhibitors such as tipelukast,

PPAR α agonists, e.g., mixed PPAR α/δ agonists such as GFT505,

PPAR gamma agonists, such as pioglitazone,

(ii) a PPAR delta agonist and a PPAR delta agonist,

rho-associated protein kinase 2(ROCK2) inhibitors, such as KD-025,

sodium glucose transporter-2 (SGLT2) inhibitors, such as remogliflozin etabonate,

stearoyl CoA desaturase-1 inhibitors, such as aramchol or CVT-12805,

thyroid hormone receptor beta agonists, such as MGL-3196,

inhibitors of the tumor necrosis factor alpha (TNF alpha) ligand,

transglutaminase inhibitors and transglutaminase inhibitor precursors, such as mercaptoethylamine,

PTPlb inhibitors, for example A119505, A220435, A321842, CPT633, ISIS-404173, JTT-551, MX-7014, MX-7091, MX-7102, NNC-521246, OTX-001, OTX-002 or TTP814, and

ASK1 inhibitors such as GS 4977.

In some embodiments, the one or more additional therapeutic agents are selected from acetylsalicylic acid, alitame (alipogene tipvovec), aramchol, atorvastatin, BLX-1002, cenicriviroc (cenicriviroc), cobiprostone, colesevelam (colesevelam), emncasan, enalapril, GFT-505, GR-MD-02, hydrochlorothiazide, ethyl eicosapentaenoate (ethyl eicosapentaenoate), IMM-124E, KD-025, linagliptin (linagliptin), liraglutide, mercaptoethylamine, MGL-3196, obeticholic acid (obeticolic acid), olyloxime (oleuroxime), polyethylene glycol-ilox, pioglitazone, GS-9674, remoglicyzin etabonate (remogliflozin etate), SHP-626, sorrel (sorrel), tryomycin (sorethrin), troloxystron, tryxlox-318, glicotion-VBY, and desoxymestran-x.

In some embodiments, one of the one or more additional therapeutic agents is selected from the group consisting of acetylsalicylic acid, alisertine, aramchol, atorvastatin, BLX-1002, and cenicriviroc.

The invention also relates to methods of selectively inhibiting the protein kinase MKK4 relative to the protein kinases JNK1 and MKK7, promoting liver regeneration or preventing liver cell death, treating acute, chronic plus acute or chronic liver diseases, or for treating: acute and chronic or chronic plus acute liver diseases, such as acute and chronic viral hepatitis, e.g. hepatitis b, c, e, hepatitis caused by epstein-barr virus, cytomegalovirus, herpes simplex virus and other viruses, all types of autoimmune hepatitis, primary sclerosing hepatitis, alcoholic hepatitis;

metabolic liver diseases such as metabolic syndrome, fatty liver such as non-alcoholic fatty liver disease (NAFL), non-alcoholic steatohepatitis (NASH), Alcoholic Steatohepatitis (ASH), wilson's disease, hemochromatosis, alpha 1-antitrypsin deficiency, glycogen storage disease;

all types of cirrhosis, such as primary biliary cirrhosis, alcoholic toxic cirrhosis, cryptogenic cirrhosis;

Acute (fulminant) or chronic liver failure, such as toxic liver failure, e.g. acetaminophen (paracetamol) -induced liver failure, alpha-amanitin-induced liver failure, e.g. drug-induced liver toxicity and liver failure caused by antibiotics, non-steroidal anti-inflammatory drugs, anticonvulsants, acute liver failure induced by herbal supplements (kava, ephedra, scutellaria, mint, etc.), liver disease and liver failure caused by vascular diseases such as bulgan syndrome, acute liver failure of unknown cause, chronic liver disease caused by right heart failure;

galactosemia, cystic fibrosis, porphyria, ischemic perfusion injury of the liver, posthepatic steatosis syndrome, primary sclerosing cholangitis or hepatic encephalopathy,

the method comprises administering to a subject in need thereof an effective amount of an MKK4 inhibitor or compound or composition as defined above.

In one embodiment, the compounds of the invention are administered at a dose of 0.2 to 15mg/kg or 0.5 to 12mg/kg for the subject to be treated. The compound may be administered once or several times a day. The compound is administered for 4 to 12 weeks.

The following examples illustrate the invention without limiting it.

Examples

Abbreviations:

ATP adenosine triphosphate

Boc₂O di-tert-butoxycarbonate

CDE 1, 2-Dimethylpropylamine

CPME Cyclopentylmethyl Ether

DCE Dichloroethane

DCM dichloromethane

DIPEA diisopropylethylamine

(4-) DMAP (4-) dimethylaminopyridine

DME dimethyl ether

DMF dimethyl formamide

DMSO dimethyl sulfoxide

DPPA Azidophosphoric acid Diphenyl ester

DTT dithiothreitol

EtOAc ethyl acetate

HEPES 2- (4- (2-hydroxyethyl) -1-piperazinyl) -ethanesulfonic acid

HOBt hydroxybenzotriazole

HPLC high performance liquid chromatography

IPA isopropyl alcohol

LAH lithium aluminum hydride

LDA lithium diisopropylamide

mCPBA m-chloroperoxybenzoic acid

MeCN acetonitrile

MeOH methanol

NIS N-iodosuccinimide

Pd₂(dba₃) Tris (dibenzylideneacetone) dipalladium (0)

Pd(dppf)Cl₂[1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride

PE Petroleum Ether

PMBCl p-methoxybenzyl chloride

Rt or RT at room temperature

Sol solution

TEA Triethanolamine

TfOH triflic acid

THF tetrahydrofuran

TLC thin layer chromatography

Xantphos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (4,5-bis (diphenylphosphino) -9,9-dimethylxanthene)

Example 1: propane-1-sulfonic acid [3- (5-chloro-1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluoro-phenyl } amide, prepared as disclosed in WO 2007/002433:

example 2: propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl ] -2, 4-difluoro-phenyl } -amide, prepared as disclosed in WO 2007/002433:

for the preparation of the compounds of the invention, the General Procedures (GP) aa to ae are used:

general procedure aa:

oxalyl chloride (1.1 eq) was added to a suspension of carboxylic acid (1.0 eq) in anhydrous DCM (0.5 m). A few drops of DMF were added and the resulting mixture was stirred at room temperature until gas formation was complete. Excess MeOH was added to the solution and the solvent was evaporated under reduced pressure. The residue was dried in vacuo and the product was used without further purification.

General procedure ab:

Pd/C (0.1 equiv.) was added to a solution of nitrobenzene (1.0 equiv.) in EtOH (0.2 m). Subjecting the suspension to H₂The reaction was degassed and stirred at room temperature to completely consume the starting material. The mixture was then passed through a pad of celite, and the filtrate was concentrated in vacuo. The product was used without further purification.

General procedure ac:

aniline (1.0 eq.) and Et₃A solution of N (2.2 equiv.) in anhydrous DCM (0.25m) was cooled to 0 ℃ and the corresponding sulfonyl chloride was added dropwise. After the addition was complete, the ice bath was removed and the solution was stirred at room temperature for about 1 hour. The solution was then diluted with water, extracted with EtOAc, and the combined organic layers were taken over Na₂SO₄And (5) drying. Removing the solvent under reduced pressure, and performing flash chromatography (SiO)₂nHex/EtOAc 9/1).

The ester/disulfonamide was dissolved in THF/MeOH (1M, 4:1), cooled to 0 deg.C and treated with aqueous NaOH (2M, 2-3 equivalents). After 10 min, the ice bath was removed and the reaction was stirred at room temperature until complete hydrolysis. THF/MeOH was removed in vacuo, the residue was treated with aqueous HCl (2m), the product was precipitated, and the precipitate was filtered, dried, and used without any further purification.

General procedure ad:

aryl bromide (1 equivalent), K₂CO₃(2 equiv.) and boric acid/pinacol ester (1.2 equiv.) suspended in DME/H₂O (0.15m, 4:1) and degassed with argon for 10 min. Adding Pd (PPh) to the suspension₃)₄(0.05 eq) and then irradiated at 130 ℃ for 30 minutes (. mu.w). The resulting mixture was passed through a celite pad, and the solvent was removed under reduced pressure. Crude mixture was purified by flash chromatography (SiO) ₂DCM/MeOH (MeOH content increased from 0% (v/v) to 5% (v/v) in 0.5% steps) to afford the title compound.

General procedure ae:

the carboxylic acid (1.1 eq) was suspended in dry DCM (0.5m) and oxalyl chloride (1.05 eq) was added in succession with a few drops of DMF. After gas formation had ceased, the resulting solution was added dropwise to azaindole (1 equivalent) and AlCl₃(5 equiv.) in suspension in anhydrous DCM (0.5 m). The mixture was stirred at room temperature for 0.5 to 3 hours. Adding saturated NH₄Aqueous Cl to quench the reaction. The aqueous phase was extracted with EtOAc (3X), and the combined organic layers were extracted with Na₂SO₄Drying and evaporating the solvent under reduced pressure. By flash chromatography (SiO)₂The product was purified either nHex/EtOAc 1:1 or DCM/MeOH (MeOH content increased in 0.5% steps from 0% (v/v) to 3% (v/v)) to give the title compound.

2, 6-difluoro-3-nitrobenzoic acid methyl ester

The process is as follows: according toGP aaThe title compound was obtained.

Yield: 2.1g, 9.4mmol, 96% (white solid)

TLC：PE/EtOAc 3/1

¹H NMR(DMSO-d₆,200MHz,ppm):δ8.45(td,J＝9.0,5.6Hz,1H),7.52(td,J＝9.4, 1.8Hz,1H),3.95(s,3H)；¹³C NMR(DMSO-d₆,50Hz,ppm):δ162.1(dd,J＝263.5,5.7 Hz),159.7,153.6(dd,J＝271.1,7.6Hz),134.4(dd,J＝7.5,4.1Hz),130.6(dd,J＝12.0,1.5 Hz),113.4(dd,J＝23.8,4.4Hz),112.2(dd,J＝20.3,18.0Hz),53.6。

3-amino-2, 6-difluorobenzoic acid methyl ester

The process is as follows: according toGP abThe title compound was obtained.

Yield: 1.8g, 9.7mmol, 98%

TLC：PE/EtOAc 3:1

2, 6-difluoro-3- (N- (propylsulfonyl) propylsulfonylamino) benzoic acid methyl ester

The process is as follows: according toFirst part of GP acThe title compound was obtained.

Yield: 8.86g, 22.2mmol, 90%

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ7.95(td,J＝8.8,5.8Hz,1H),7.40(t,J＝8.9 Hz,1H),3.92(s,3H),3.67(td,J＝7.3,4.2Hz,4H),1.92–1.70(m,4H),1.01(t,J＝7.4Hz, 6H)；¹³C NMR(DMSO-d₆,50Hz,ppm):δ161.42(dd,J＝143.7,6.7Hz),160.25(t,J＝1.3 Hz),156.25(dd,J＝145.2,6.7Hz),137.45(d,J＝11.1Hz),118.81(dd,J＝14.0,4.1Hz), 113.20(dd,J＝23.1,4.0Hz),111.17(dd,J＝19.8,17.9Hz),57.0,53.3,16.4,12.4.TLC-MS: C₁₄H₁₉F₂NO₆S₂([M-H]^-) Calculated value of m/z of (1): 398.4, found 398.3.

2, 6-difluoro-3- (propylsulfonylamino) benzoic acid

The process is as follows: according toSecond part of GP acThe title compound was obtained.

Yield: 1.2g, 4.2mmol, 55%

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ14.01(s,1H),9.74(s,1H),7.54(dd,J＝14.8, 8.7Hz,1H),7.20(t,J＝9.2Hz,1H),3.15–3.02(m,2H),1.85–1.63(m,2H),0.97(t,J＝ 7.4Hz,3H)；¹³C NMR(DMSO-d₆,50Hz,ppm):δ161.8,157.3(dd,J＝174.8,6.9Hz), 152.3(dd,J＝178.1,6.9Hz),129.8(dd,J＝10.2,2.2Hz),122.0(dd,J＝13.5,3.8Hz), 112.8(dd,J＝21.3,19.3Hz),112.3(dd,J＝22.6,4.1Hz),53.8,16.9,12.6.TLC-MS: C₁₀H₁₁F₂NO₄S([M-H]^-) Calculated value of (2) m/z is 278.0, found value is 278.0.

N- (3- (5-bromo-1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonamide

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 1.8g, 3.9mmol, 77%

TLC：PE/EtOAc 50％

¹H NMR(DMSO-d₆,200MHz,ppm):δ13.14(s,1H),9.78(s,1H),8.59(d,J＝1.8Hz, 1H),8.51(d,J＝2.0Hz,1H),8.28(s,1H),7.59(td,J＝9.0,6.4Hz,1H),7.28(t,J＝8.8Hz, 1H),3.19–3.06(m,2H),1.86–1.62(m,2H),0.96(t,J＝7.3Hz,3H).；¹³C NMR (DMSO-d₆,50Hz,ppm):δ180.6,156.6(dd,J＝184.1,7.6Hz),151.7(dd,J＝187.1,7.7 Hz),147.8,145.3,139.3,131.1,128.9(dd,J＝10.1,2.1Hz),122.0(dd,J＝13.6,3.8Hz), 119.0,117.8(dd,J＝24.3,22.1Hz),114.9,114.3,112.4(dd,J＝22.8,3.8Hz),53.5,16.8,12.6. TLC-MS:C₁₇H₁₄BrF₂N₃O₃S([M-H]^-) The calculated value of (b) is 456.0, and the found value is 456.1.

5- (4-chlorophenyl) -1H-pyrrolo [2,3-b]Pyridine compound

The process is as follows: reacting 5-bromo-1H-pyrrolo [2,3-b ]]Pyridine (2g, 10.2mmol, 1.0 equiv.), K₂CO₃(2.8g, 20.3mmol, 2 equiv.) and (4-chlorophenyl) boronic acid (1.8g, 11.2mmol, 1.1 equiv.) were suspended in DME/H₂O(30ml，4:1) and degassed with argon. Adding Pd (PPh)₃)₄(587mg, 508. mu. mol, 0.05 eq.) and the reaction mixture is heated at reflux until complete consumption of the starting material. The resulting solution was passed through a pad of celite, diluted with EtOAc and washed with water. The combined organic layers were washed with Na₂SO₄Drying and evaporating the solvent under reduced pressure. By flash chromatography (SiO)₂nHex/EtOAc 6:4) purifying the crude product.

Yield: 2.23g, 9.4mmol, 92% (white solid).

TLC：PE/EtOAc 1:1

¹H NMR(DMSO-d₆,200MHz,ppm):δ11.76(s,1H),8.51(d,J＝2.1Hz,1H),8.20(d, J＝1.9Hz,1H),7.72(d,J＝8.5Hz,2H),7.57–7.43(m,3H),6.50(dd,J＝3.2,1.7Hz, 1H).；¹³C NMR(DMSO-d₆,50Hz,ppm):δ148.2,141.4,138.0,131.7,128.9,128.6,127.1, 126.9,126.1,119.7,100.2。

Example 3: the above N- (2, 4-difluoro-3- (5- (4-methoxyphenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl Yl) phenyl) propane-1-sulfonamide

The process is as follows: according toGP adThe title compound was obtained.

Yield: 22.7mg, 47. mu. mol, 36% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.96(s,1H),9.78(s,1H),8.67(d,J＝1.7Hz, 1H),8.57(s,1H),8.21(s,1H),7.68(d,J＝8.5Hz,2H),7.59(dd,J＝14.8,8.9Hz,1H),7.28 (t,J＝8.5Hz,1H),7.08(d,J＝8.6Hz,2H),3.82(s,3H),3.19–3.06(m,2H),1.74(dq, J＝14.7,7.2Hz,2H),0.96(t,J＝7.4Hz,3H)；¹³C NMR(DMSO-d₆,101Hz,ppm):δ180.5, 159.0,156.0(dd,J＝246.6,6.9Hz),152.4(dd,J＝258.5,8.9Hz),148.5,143.7,138.4,131.3, 130.4,128.7(d,J＝8.7Hz),128.2,126.4,121.9(dd,J＝13.1,3.6Hz),118.2(dd,J＝25.0, 23.0Hz),117.5,115.6,114.6,112.2(dd,J＝22.5,3.3Hz),55.2,53.5,16.74,12.5.TLC-MS: C₂₄H₂₁F₂N₃O₄S([M-H]^-) 484.1, found: 484.2.

example 4: n- (3- (5- (4-cyanophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorobenzene Yl) propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 31mg, 65. mu. mol, 49% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.10(s,1H),9.79(s,1H),8.80(d,J＝2.1Hz, 1H),8.73(s,1H),8.29(s,1H),8.00(d,J＝8.6Hz,2H),7.97(d,J＝8.5Hz,2H),7.60(dd,J ＝14.8,8.9Hz,1H),7.29(t,J＝8.5Hz,1H),3.17–3.09(m,2H),1.81–1.68(m,2H),0.97 (t,J＝7.4Hz,3H)；¹³C NMR(DMSO-d₆,101Hz,ppm):δ180.6,156.0(dd,J＝246.8,6.7 Hz),152.4(dd,J＝249.8,8.7Hz),149.4,144.2,142.8,139.0,132.9,131.4(d,J＝9.6Hz), 129.7,128.7(t,J＝11.5Hz),128.0,127.6,121.9(dd,J＝13.2,2.7Hz),118.8,118.1(dd,J＝ 24.9,22.1Hz),117.5,115.8,112.3(dd,J＝22.7,3.6Hz),110.1,53.6,16.8,12.5.TLC-MS: C₂₄H₁₈F₂N₄O₃S([M-H]^-) Calculated value of (2) m/z was 479.1, found value was 479.2.

Example 5: n- (2, 4-difluoro-3- (5- (thiophen-2-yl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) benzene Yl) propane-1-sulfonamides

The process is as follows: according toGP adGet markThe title compound.

Yield: 48mg, 104. mu. mol, 79% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.04(s,1H),9.79(s,1H),8.78(d,J＝2.2Hz, 1H),8.60(s,1H),8.24(s,1H),7.65–7.53(m,3H),7.29(t,J＝8.7Hz,1H),7.20(dd,J＝5.0, 3.7Hz,1H),3.16–3.08(m,2H),1.80–1.68(m,2H),0.96(t,J＝7.4Hz,3H).；¹³C NMR (DMSO-d₆,101Hz,ppm):δ180.6,156.0(dd,J＝246.4,7.1Hz),152.3(dd,J＝249.6,8.4 Hz),148.7,142.7,140.7,138.7,128.8(d,J＝10.2Hz),128.7,126.0,125.5,124.1,121.9(dd, J＝13.8,4.0Hz),117.5,115.5,112.3(dd,J＝22.6,3.0Hz),53.5,16.8,12.5.TLC-MS: C₂₁H₁₇F₂N₃O₃S₂([M-H]^-) The calculated value of (1) m/z was 461.1, and the found value was 461.2.

Example 6: n- (2, 4-difluoro-3- (5- (quinolin-3-yl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) benzene Yl) propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 42mg, 84. mu. mol, 64% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.10(s,1H),9.80(s,1H),9.34(d,J＝2.2Hz, 1H),8.93(d,J＝2.2Hz,1H),8.86(s,1H),8.79(d,J＝1.9Hz,1H),8.31(s,1H),8.11(dd,J ＝13.0,8.1Hz,2H),7.84–7.77(m,1H),7.68(t,J＝7.5Hz,1H),7.60(td,J＝9.0,6.0Hz, 1H),7.30(t,J＝8.7Hz,1H),3.17–3.09(m,2H),1.81–1.68(m,2H),0.96(t,J＝7.4Hz, 3H)；¹³C NMR(DMSO-d₆,101Hz,ppm):δ180.7,156.1(dd,J＝247.4,6.2Hz),152.4(dd, J＝249.7,8.4Hz),149.6,149.2,146.8,144.4,139.1,133.5,131.1,129.7,128.8(d,J＝9.7 Hz),128.7,128.5,128.4,127.7,127.1,122.0(dd,J＝13.8,3.8Hz),118.2(dd,J＝25.6,20.8 Hz),117.6,115.8,112.4(dd,J＝22.8,3.4Hz),53.5,16.8,12.6.TLC-MS:C₂₆H₂₀F₂N₄O₃S ([M-H]^-) The calculated value of m/z of (2) is 505.1, and the measured value is 505.1.

Example 7: n- (2, 4-difluoro-3- (5- (4-isopropylphenyl) -1H-pyrrolo [2, 3-b) ]Pyridine-3-carbonyl) Phenyl) propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 39mg, 78. mu. mol, 60% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.99(s,1H),9.79(s,1H),8.69(d,J＝2.1Hz, 1H),8.60(s,1H),8.23(s,1H),7.66(d,J＝8.1Hz,2H),7.59(td,J＝9.0,6.0Hz,1H),7.39 (d,J＝8.2Hz,2H),7.29(t,J＝8.4Hz,1H),3.16–3.08(m,2H),2.95(sept,1H),1.80– 1.68(m,2H),1.25(d,J＝6.9Hz,6H),0.96(t,J＝7.4Hz,3H)；¹³C NMR(DMSO-d₆,101 Hz,ppm):δ180.6,156.0(dd,J＝246.7,6.9Hz),152.3(dd,J＝250.0,8.0Hz),148.7,147.8, 143.9,138.5,135.6,131.5,128.73(d,J＝9.5Hz),127.1,127.0,126.7,121.9(dd,J＝13.7, 3.3Hz),118.2(dd,J＝24.5,22.9Hz),117.5,115.6,112.3(dd,J＝22.5,3.1Hz),53.5,33.1, 23.8,16.8,12.6.TLC-MS:C₂₆H₂₅F₂N₃O₃S([M-H]^-) The calculated value of (2) is 496.2, found is 496.1.

Example 8: n- (2, 4-difluoro-3- (5- (4- (methylthio) phenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl Yl) phenyl) propane-1-sulfonamide

The process is as follows: according toGP adThe title compound was obtained.

Yield: 47mg, 93. mu. mol, 71% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.00(s,1H),9.78(s,1H),8.70(d,J＝2.1Hz, 1H),8.62(s,1H),8.23(s,1H),7.71(d,J＝8.3Hz,2H),7.63–7.56(m,1H),7.40(d,J＝8.3 Hz,2H),7.29(t,J＝8.7Hz,1H),3.16–3.09(m,2H),2.53(s,3H),1.80–1.69(m,2H), 0.96(t,J＝7.4Hz,3H)；¹³C NMR(DMSO-d₆,101MHz,ppm):δ180.6,156.0(dd,J＝246.7, 7.0Hz),152.3(dd,J＝249.8,8.8Hz),148.8,143.8,138.6,137.7,134.6,131.4(d,J＝9.8 Hz),130.9,128.7(dd,J＝10.9,4.2Hz),127.5,126.6,121.92(dd,J＝13.4,3.2Hz),118.2 (dd,J＝24.5,22.8Hz),117.5,115.7,112.3(dd,J＝22.5,3.2Hz),53.5,16.8,14.7,12.6. TLC-MS:C₂₄H₂₁F₂N₃O₃S₂([M-H]^-) The calculated value of m/z of (2) was 500.1, and the found value was 500.0.

Example 9: n- (2, 4-difluoro-3- (5- (2-hydroxyphenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) benzene Yl) propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 30mg, 64. mu. mol, 49% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.91(s,1H),9.77(s,1H),9.69(s,1H),8.62(s, 1H),8.54(d,J＝2.1Hz,1H),8.18(s,1H),7.58(td,J＝9.0,5.9Hz,1H),7.36(dd,J＝7.5, 1.2Hz,1H),7.28(t,J＝8.4Hz,1H),7.25–7.20(m,1H),7.00(d,J＝7.7Hz,1H),6.94(t,J ＝7.4Hz,1H),3.15–3.09(m,2H),1.80–1.68(m,2H),0.96(t,J＝7.4Hz,3H).；¹³C NMR (DMSO-d₆,101Hz,ppm):δ180.5,156.0(dd,J＝246.5,6.9Hz),154.4,152.27(dd, J＝249.5,8.8Hz),148.1,145.7,138.1,130.6,129.5,129.5,128.8,128.69–128.44(m),125.3, 121.9(dd,J＝13.2,3.5Hz),119.6,118.2(t,J＝23.8Hz),116.9,116.0,115.6,112.2(dd,J＝ 23.1,3.9Hz),53.5,16.7,12.5.TLC-MS:C₂₃H₁₉F₂N₃O₄S([M-H]^-) The calculated value of (b) is 470.1, and the found value is 470.4.

Example 10: n- (3- (5- (benzo [ d ]))][1,3]Dioxolen-5-yl) -1H-pyrrolo [2,3-b]Pyridine (II) Pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonamide

The process is as follows: according toGP adThe title compound was obtained.

Yield: 59mg, 119. mu. mol, 91% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.96(s,1H),9.77(s,1H),8.64(d,J＝2.0Hz, 1H),8.56(s,1H),8.20(s,1H),7.67–7.50(m,1H),7.33(s,1H),7.28(t,J＝8.7Hz,1H), 7.20(dd,J＝8.1,1.1Hz,1H),7.05(d,J＝8.0Hz,1H),6.09(s,2H),3.17–3.08(m,2H), 1.82–1.69(m,2H),0.97(t,J＝7.4Hz,3H)；¹³C NMR(DMSO-d₆,101Hz,ppm):δ180.5, 156.0(dd,J＝246.7,7.3Hz),152.3(dd,J＝249.7,8.6Hz),148.6,148.1,147.0,143.9,138.4, 132.4,131.5,128.6(d,J＝11.8Hz),126.8,122.0(dd,J＝13.8,3.4Hz),120.8,118.2(dd,J ＝24.5,22.7Hz),117.4,115.7,112.2(dd,J＝22.8,3.4Hz),108.8,107.5,101.2,53.6,16.8, 12.5.TLC-MS:C₂₄H₁₉F₂N₃O₅S([M-H]^-) Calculated value of (2) m/z is 498.1, found value is 498.3.

Example 11: n- (2, 4-difluoro-3- (5- (4-fluorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) benzene Yl) propane-1-sulfonamides

The process is as follows: according to the followingGP adThe title compound was obtained.

Yield: 55mg, 115. mu. mol, 88% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.99(s,1H),9.78(s,1H),8.69(d,J＝2.2Hz, 1H),8.62(s,1H),8.25(s,1H),7.80(dd,J＝8.6,5.4Hz,2H),7.59(td,J＝9.0,5.9Hz,1H), 7.35(t,J＝8.8Hz,2H),7.29(t,J＝8.7Hz,1H),3.15–3.10(m,2H),1.80–1.69(m,2H), 0.96(t,J＝7.4Hz,3H)；¹³C NMR(DMSO-d₆,101Hz,ppm):δ180.6,161.9(d,J＝244.6 Hz),156.0(dd,J＝246.4,6.9Hz),152.3(dd,J＝249.6,8.6Hz),148.8,143.9,138.6,134.6 (d,J＝3.0Hz),130.6,129.1(d,J＝8.2Hz),128.7(dd,J＝10.8,4.2Hz),127.0,121.9(dd,J ＝13.6,3.6Hz),118.1(dd,J＝24.4,22.6Hz),117.4,115.9(d,J＝21.4Hz),115.6,112.2(dd, J＝22.9,3.2Hz),53.5,16.8,12.5.TLC-MS:C₂₃H₁₈F₃N₃O₃S([M-H]^-) The calculated value of (2) is 472.1, and the found value is 472.3.

Example 12: n- (2, 4-difluoro-3- (5- (4-fluoro-2-methylphenyl (-1H-pyrrolo [2,3-b ]))]Pyridine-3-carbonyl Yl) phenyl) propane-1-sulfonamide

The process is as follows: according toGP adThe title compound was obtained.

Yield: 47mg, 96. mu. mol, 73% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.02(s,1H),9.78(s,1H),8.37(d,J＝1.6Hz, 1H),8.34(s,1H),8.26(s,1H),7.58(td,J＝8.9,6.1Hz,1H),7.35(dd,J＝8.3,6.2Hz,1H), 7.28(t,J＝8.7Hz,1H),7.23(dd,J＝10.1,2.4Hz,1H),7.14(td,J＝8.5,2.5Hz,1H),3.16 –3.09(m,2H),2.26(s,3H),1.80–1.69(m,2H),0.96(t,J＝7.4Hz,3H)；¹³C NMR (DMSO-d₆,101Hz,ppm):δ180.6,161.6(d,J＝244.0Hz),156.0(dd,J＝246.4,6.9Hz), 152.3(dd,J＝249.5,8.5Hz),148.4,145.4,138.5,138.2(d,J＝8.1Hz),134.9(d,J＝2.9 Hz),132.0(d,J＝8.5Hz),131.2,129.3,128.7(d,J＝9.8Hz),121.9(dd,J＝13.6,3.5Hz), 118.1(dd,J＝24.6,22.3Hz),117.0,116.73(d,J＝21.1Hz),115.5,112.7(d,J＝20.9Hz), 112.2(dd,J＝22.7,3.5Hz),53.5,20.2,16.8,12.5.TLC-MS:C₂₄H₂₀F₃N₃O₃S([M-H]^-) The calculated value of (2) is 486.1, and the found value is 486.3.

Example 13: n- (3- (5- (2-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorobenzene Yl) propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 42mg, 86. mu. mol, 66% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.07(s,1H),9.78(s,1H),8.49(s,1H),8.46 (d,J＝2.1Hz,1H),8.28(s,1H),7.66–7.54(m,3H),7.52–7.43(m,2H),7.28(t,J＝8.7 Hz,1H),3.16–3.08(m,2H),1.80–1.68(m,2H),0.96(t,J＝7.4Hz,3H)；¹³C NMR (DMSO-d₆,101Hz,ppm):δ180.6,156.0(dd,J＝246.6,7.1Hz),152.3(dd,J＝249.6,8.5 Hz),148.6,145.4,138.7,137.3,132.0,131.8,129.8,129.8,129.7,129.6,128.7(d,J＝8.4 Hz),127.6,121.9(dd,J＝13.6,3.6Hz),118.1(dd,J＝24.3,22.6Hz),116.8,115.6,112.27 (dd,J＝22.7,3.6Hz),53.5,16.8,12.5.TLC-MS:C₂₃H₁₈ClF₂N₃O₃S([M-H]^-) Calculated value of (2) m/z is 488.1, found is 488.3.

Example 14: n- (3- (5- (3-cyanophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl2, 4-difluorobenzene Yl) propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 42mg, 87. mu. mol, 67% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.06(br.s.,1H),9.79(br.s,1H),8.78(d,J＝ 2.2Hz,1H),8.73(s,1H),8.28(d,J＝7.3Hz,2H),8.12(d,J＝8.0Hz,1H),7.88(d,J＝7.7 Hz,1H),7.72(t,J＝7.8Hz,1H),7.59(td,J＝9.0,6.0Hz,1H),7.29(t,J＝8.7Hz,1H), 3.17–3.09(m,2H),1.80–1.67(m,2H),0.96(t,J＝7.4Hz,3H).¹³C NMR(DMSO-d₆,101 MHz,ppm):δ180.6,156.0(dd,J＝246.6,6.9Hz),152.4(dd,J＝249.6,8.2Hz),149.2, 144.2,139.4,138.9,132.0,131.1,130.7,130.2,129.5,128.8(d,J＝8.7Hz),127.6,121.9(dd, J＝13.6,3.4Hz),118.7,118.1(dd,J＝24.6,22.6Hz),117.4,115.8,112.3(dd,J＝22.7,3.7 Hz),112.2,53.6,16.8,12.6.TLC-MS:C₂₄H₁₈F₂N₄O₃S([M-H]^-) Calculated value of (2) m/z was 479.1, found value was 479.4.

Example 15: n- (3- (5- (2, 3-dihydrobenzo [ b ]][1,4]Dioxins (dioxins) -6-yl) -1H- Pyrrolo [2,3-b]Pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonamide

The process is as follows: according toGP adThe title compound was obtained.

Yield: 60mg, 117. mu. mol, 89% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.97(s,1H),9.79(s,1H),8.64(d,J＝2.0Hz, 1H),8.55(s,1H),8.21(s,1H),7.65–7.51(m,2H),7.28(t,J＝8.5Hz,1H),7.24–7.16(m, 2H),6.99(d,J＝8.3Hz,1H),4.29(s,4H),3.17–3.07(m,2H),1.74(dq,J＝14.9,7.4Hz, 2H),0.96(t,J＝7.4Hz,3H).¹³C NMR(DMSO-d₆,101MHz,ppm):δ180.6,156.0(dd,J＝ 246.4,7.1Hz),152.4(dd,J＝249.6,8.3Hz),148.6,143.9,143.8,143.3,138.5,131.4,131.2, 128.7(d,J＝11.8Hz),126.6,122.0(dd,J＝13.7,3.4Hz),120.0,118.24(dd,J＝24.2,22.1 Hz),117.8,117.5,115.7,115.6,112.3(dd,J＝23.0,3.6Hz),64.2,64.2,53.6,16.8,12.6. TLC-MS:C₂₅H₂₁F₂N₃O₅S([M-H]^-) The calculated value of (b) was 512.1, and the found value was 512.4.

Example 16: n- (3- (5- (3, 4-difluorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluoro Phenyl) propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 51mg, 104. mu. mol, 80% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.04(s,1H),9.79(s,1H),8.72(d,J＝2.1Hz, 1H),8.65(s,1H),8.26(s,1H),7.89(ddd,J＝9.7,7.7,1.5Hz,1H),7.65–7.50(m,3H),7.29 (t,J＝8.4Hz,1H),3.16–3.09(m,2H),1.74(dq,J＝14.9,7.4Hz,2H),0.96(t,J＝7.4Hz, 3H).TLC-MS:C₂₃H₁₇F₄N₃O₃S([M-H]^-) The calculated value of m/z of (2) is 490.1, and the found value is 490.1.

Example 17: n- (3- (5- (3, 4-difluorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluoro Phenyl) propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 35mg, 79. mu. mol, 60% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.02(s,1H),9.79(s,1H),8.83(d,J＝2.1Hz, 1H),8.70(s,1H),8.23(d,J＝1.2Hz,1H),7.82(d,J＝1.1Hz,1H),7.59(td,J＝8.9,6.0Hz, 1H),7.29(t,J＝8.4Hz,1H),7.10(d,J＝3.2Hz,1H),6.65(dd,J＝3.3,1.8Hz,1H),3.17– 3.07(m,2H),1.74(dq,J＝14.9,7.4Hz,2H),0.96(t,J＝7.4Hz,3H).¹³CNMR(DMSO-d₆, 101MHz,ppm):δ180.6,156.0(dd,J＝246.6,6.7Hz),152.3(dd,J＝249.4,8.1Hz),151.3, 148.5,143.2,141.5,138.6,128.8(d,J＝9.8Hz),123.5,122.3,121.9(dd,J＝13.3,3.8Hz), 118.5–117.8(m),117.3,115.7,112.5–112.2(m),112.2,105.9,53.5,16.8,12.6.TLC-MS: C₂₁H₁₇F₂N₃O₄S([M-H]^-) Calculated value of (2) m/z is 444.1, found value is 444.1.

Example 18: n- (2, 4-difluoro-3- (5- (naphthalen-1-yl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) phenyl group) Propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 50mg, 98. mu. mol, 75% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.11(s,1H),9.80(s,1H),8.52(s,1H),8.51(s, 1H),8.30(s,1H),8.03(t,J＝8.5Hz,2H),7.80(d,J＝8.1Hz,1H),7.66–7.50(m,5H), 7.28(t,J＝8.7Hz,1H),3.15–3.08(m,2H),1.79–1.67(m,2H),0.96(t,J＝7.4Hz,3H). ¹³C NMR(DMSO-d₆,101MHz,ppm):δ180.7,156.1(dd,J＝246.4,6.8Hz),152.4(dd,J＝ 249.5,8.5Hz),148.8,145.9,138.8,136.6,133.5,131.3,131.0,130.1,128.8(d,J＝8.6Hz), 128.5,128.1,127.9,126.8,126.1,125.7,125.0,122.0(dd,J＝13.7,3.4Hz),118.6–117.7 (m),117.2,115.7,112.35(dd,J＝23.1,3.3Hz),53.6,16.8,12.6.TLC-MS:C₂₇H₂₁F₂N₃O₃S ([M-H]^-) The calculated value of m/z of (2) is 504.1, and the found value is 504.2.

Example 19: n- (3- (5- (3-aminophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorobenzene Yl) propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 33mg, 69. mu. mol, 53% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.97(s,1H),9.79(s,1H),8.62(d,J＝1.7Hz, 1H),8.59(s,1H),8.21(s,1H),7.59(td,J＝8.9,6.1Hz,1H),7.29(t,J＝8.6Hz,1H),7.16(t, J＝7.8Hz,1H),6.94(s,1H),6.86(d,J＝7.5Hz,1H),6.62(dd,J＝8.0,1.0Hz,1H),5.26(s, 2H),3.16–3.06(m,2H),1.81–1.66(m,2H),0.96(t,J＝7.4Hz,3H).¹³C NMR(DMSO-d₆, 101MHz,ppm):δ180.6,156.0(dd,J＝246.5,7.2Hz),152.4(dd,J＝250.2,8.1Hz),149.3, 148.8,143.8,138.7,138.5,132.3,129.7,129.0–128.5(m),126.7,122.0(dd,J＝13.6,3.5 Hz),118.7–117.8(m),117.5,115.7,114.6,113.3,112.4,112.2(d,J＝3.8Hz),53.6,16.8, 12.6.TLC-MS:C₂₃H₂₀F₂N₄O₃S([M-H]^-) 469.1, found 469.2.

Example 20: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorobenzene Alkyl) ethanesulfonamides

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 40mg, 85. mu. mol, 29% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,200MHz,ppm):δ13.03(s,1H),9.79(s,1H),8.71(d,J＝2.0Hz, 1H),8.64(s,1H),8.26(s,1H),7.80(d,J＝8.5Hz,2H),7.60(m,3H),7.28(t,J＝8.5Hz, 1H),3.15(q,7.4Hz,2H),1.26(t,J＝7.2Hz,3H).TLC-MS:C₂₂H₁₆ClF₂N₃O₃S([M-H]^-) The calculated value of m/z of (2) was 474.1, and the found value was 474.1.

Example 21: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorobenzene Alkyl) methanesulfonamides

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 41mg, 89. mu. mol, 30% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.03(s,1H),9.76(s,1H),8.71(d,J＝2.1Hz, 1H),8.66(s,1H),8.27(s,1H),7.80(d,J＝8.5Hz,2H),7.63–7.54(m,3H),7.30(t, J＝8.6Hz,1H),3.08(s,3H).¹³C NMR(DMSO-d₆,101Hz,ppm):δ180.6,156.1(dd,J＝ 247.3,6.8Hz),152.6(dd,J＝249.8,8.7Hz),149.0,144.0,138.9,137.0,132.5,130.2,129.0, 128.9,127.5(dd,J＝35.1,2.0Hz),127.1,121.9(dd,J＝13.4,3.8Hz),118.2(dd,J＝24.9, 22.5Hz),117.5,115.7,112.3(dd,J＝23.3,4.0Hz).TLC-MS:C₂₁H₁₄ClF₂N₃O₃S([M-H]^-) Calculated value of (d) is 460.0, found value is 460.0.

Example 22: n- (3- (5- (4-chloro)Phenyl) -1H-pyrrolo [2,3-b]Pyridine-3-carbonyl) -2, 4-difluorobenzene Yl) butane-1-sulfonamides

Step 1

Step 2

Step 1: 3- (Butylsulfonylamino) -2, 6-difluorobenzoic acid

The process is as follows: according toGP acThe title compound was obtained.

Yield: after 2 steps 211mg, 720. mu. mol, 72% (off-white solid)

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ14.05(s,1H),9.75(s,1H),7.54(td,J＝9.1, 6.3Hz,1H),7.20(t,J＝9.2Hz,1H),3.16–3.04(m,2H),1.80–1.58(m,2H),1.51–1.26 (m,2H),0.86(t,J＝7.2Hz,3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ161.8,157.3(dd,J＝ 175.0,6.8Hz),152.3(dd,J＝178.3,6.9Hz),129.8(dd,J＝10.1,2.2Hz),122.0(dd,J＝ 13.5,3.8Hz),112.8(dd,J＝21.3,19.3Hz),112.3(dd,J＝22.6,4.1Hz),51.8,25.2,20.8, 13.5.TLC-MS:C₁₁H₁₃F₂NO₄S([M-H]^-) Calculated value of (2) m/z is 292.1, found value is 292.1.

Step 2: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorophenyl) butan Alkane-1-sulfonamides

The process is as follows: according to GP aeThe title compound was obtained.

Yield: 49mg, 97. mu. mol, 37% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.03(s,1H),9.78(s,1H),8.71(d,J＝2.1Hz, 1H),8.64(s,1H),8.26(s,1H),7.79(d,J＝8.5Hz,2H),7.64–7.51(m,3H),7.29(t,J＝8.6 Hz,1H),3.17–3.07(m,2H),1.70(dt,J＝15.2,7.6Hz,2H),1.43–1.30(m,2H),0.85(t,J ＝7.3Hz,3H).¹³C NMR(DMSO-d₆,101Hz,ppm):δ180.6,156.0(dd,J＝246.6,7.1Hz), 152.3(dd,J＝249.7,8.5Hz),149.0,143.9,138.8,137.0,132.5,130.2,129.0,128.9,128.7 (m),127.0,121.9(dd,J＝13.8,3.4Hz),118.51–117.74(m),117.4,115.7,112.3(dd,J＝ 23.1,3.5Hz),51.6,25.0,20.7,13.4).TLC-MS:C₂₄H₂₀ClF₂N₃O₃S([M-H]^-) The calculated value of (b) is 502.1, and the actual value is 502.0.

Example 23: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorobenzene 2-methylpropane-1-sulfonamide

Step 1

Step 2

Step 1: 3- (Butylsulfonamido) -2, 6-difluorobenzoic acid

The process is as follows: according toGP acThe title compound was obtained.

Yield: after 2 steps 192mg, 655. mu. mol, 66% (off-white)

TLC；PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ14.10(s,1H),9.76(s,1H),7.54(td,J＝9.0, 5.9Hz,1H),7.20(td,J＝9.1,1.5Hz,1H),3.01(d,J＝6.5Hz,2H),2.28–2.04(m,1H), 1.02(d,J＝6.7Hz,6H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ161.8,157.3(dd,J＝177.4, 6.9Hz),152.2(dd,J＝180.7,6.9Hz),129.7(dd,J＝10.1,2.1Hz),122.0(dd,J＝13.4,3.8 Hz),112.8(dd,J＝21.3,19.2Hz),112.3(dd,J＝22.6,4.1Hz),59.6,24.4,22.1.TLC-MS: C₁₁H₁₃F₂NO₄S([M-H]^-) Calculated value of (2) m/z 292.1, found 292.0

Step 2: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorophenyl) - 2-methylpropane-1-sulfonamide

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 77mg, 153. mu. mol, 58% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.03(s,1H),9.79(s,1H),8.71(d,J＝2.2Hz, 1H),8.65(s,1H),8.26(d,J＝1.6Hz,1H),7.79(d,J＝8.5Hz,1H),7.64–7.53(m,1H), 7.29(t,J＝8.6Hz,1H),3.05(d,J＝6.4Hz,1H),2.26–2.09(m,1H),1.02(d,J＝6.7Hz, 1H).¹³C NMR(DMSO-d₆,101Hz,ppm):δ180.6,156.0(dd,J＝246.7,6.9Hz),152.2(dd, J＝249.5,8.8Hz),149.0,143.9,138.7,137.0,132.5,130.2,129.0,128.9,128.6(d,J＝8.8 Hz),127.0,121.9(dd,J＝13.5,2.9Hz),118.1(dd,J＝24.3,22.0Hz),117.4,115.7,112.3 (dd,J＝23.2,3.1Hz),59.4,24.3,22.0.TLC-MS:C₂₄H₂₀ClF₂N₃O₃S([M-H]^-) The calculated value of (2) is 502.1, and the found value is 501.9.

Example 24: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -5-methylphenyl) Propane-1-sulfonamides

Step 1: 3-methyl-5-nitrobenzoic acid methyl ester

The process is as follows: according toGP aaThe title compound was obtained.

Yield: 535mg, 2.7mmol, 99% (beige solid)

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ8.40–8.36(m,1H),8.30(m,1H),8.17–8.13 (m,1H),3.90(s,3H),2.49(s,3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ164.6,147.8,141.1, 135.6,130.9127.8,120.8,52.7,20.4。

Step 2: 3-amino-5-methylbenzoic acid methyl ester

The process is as follows: according toGP abThe title compound was obtained.

Yield: 446mg, 2.7mmol, 99% (dark yellow oil)

TLC：PE/EtOAc 25％

And 3, step 3: 3-methyl-5- (propylsulfonylamino) benzoic acid

The process is as follows: according toGP acThe title compound was obtained. Except that the reaction mixture was heated to reflux for at least 8 hours in the first step, and then subjected to conventional post-treatment.

Yield: 461mg, 1.8mmol, 65% (off-white solid)

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ12.99(s,1H),9.93(s,1H),7.62(s,1H),7.48(s, 1H),7.25(s,1H),3.14–2.99(m,2H),2.33(s,3H),1.81–1.52(m,2H),0.93(t,J＝7.5Hz, 3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ167.02,139.20,138.69,131.80,125.10,123.82, 117.14,52.42,21.00,16.86,12.54.TLC-MS:C₁₁H₁₅NO₄S([M-H]^-) Calculated value of (2) m/z is 256.1, found value is 256.0.

And 4, step 4: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -5-methylphenyl) propane Alkane-1-sulfonamides

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 61mg, 131. mu. mol, 50% (white solid)

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.82(s,1H),9.96(s,1H),8.72(d,J＝1.9Hz, 1H),8.68(d,J＝2.0Hz,1H),8.16(d,J＝2.8Hz,1H),7.77(d,J＝8.5Hz,2H),7.56(d,J＝ 8.4Hz,2H),7.49(s,1H),7.37(s,1H),7.27(s,1H),3.20–3.04(m,2H),2.39(s,3H),1.71 (dq,J＝14.9,7.4Hz,2H),0.95(t,J＝7.4Hz,3H).¹³C NMR(DMSO-d₆,101Hz,ppm):δ 189.2,148.7,143.4,140.4,139.2,138.5,137.3,136.5,132.3,129.6,129.0,128.8,127.6, 124.2,122.6,118.7,116.7,113.8,52.6,21.1,16.8,12.5.TLC-MS:C₂₄H₂₂ClN₃O₃S([M-H]^-) Calculated value of (2) m/z is 466.1, found value is 466.0.

Example 25: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2-methylphenyl) propane-1-sulfonamide

Step 1: 2-methyl-3-nitrobenzoic acid methyl ester

The process is as follows: according toGP aaThe title compound was obtained.

Yield: 1.1g, 5.5mmol, 99% (pale yellow solid)

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ8.03(t,J＝8.0Hz,2H),7.56(t,J＝7.9Hz, 1H),3.89(s,3H),2.49(s,3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ166.5,151.5,133.3, 133.1,131.2,127.3,126.7,52.7,15.5。

Step 2: 3-amino-2-methylbenzoic acid methyl ester

The process is as follows: according toGP abThe title compound was obtained.

Yield: 0.9g, 5.3mmol, 99% (brown oil)

TLC：PE/EtOAc 25％

And step 3: 2-methyl-3- (propylsulfonylamino) benzoic acid methyl ester

The process is as follows: methyl 3-amino-2-methylbenzoate (914mg, 5.5mmol, 1 eq) was dissolved in DCM (0.25m) To (1), pyridine (980. mu.l, 12.2mmol, 2.2 equiv.) is added and the solution is treated with propane-1-sulfonyl chloride (1.4ml, 12.2mmol, 2.2 equiv.). The resulting solution was refluxed overnight and then cooled to room temperature. Water was added to quench the reaction; the mixture was extracted with EtOAc and the combined organic layers were extracted with Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (SiO)₂nHex/EtOAc 20%) was purified.

Yield: 1.4g, 5.2mmol, 94% (light yellow oil).

TLC:PE/EtOAc 25％

¹H NMR(CDCl₃,200MHz,ppm):δ7.66(dd,J＝7.9,2.4Hz,2H),7.26(t,J＝7.9Hz, 1H),6.50(s,1H),3.90(s,3H),3.13–3.00(m,2H),2.51(s,3H),1.97–1.75(m,2H),1.03(t, J＝7.4Hz,3H).¹³C NMR(CDCl₃,50Hz,ppm):δ168.2,136.1,132.4,131.5,127.8,126.7, 126.4,54.4,52.4,17.4,15.0,13.1.TLC-MS:C₁₂H₁₇NO₄S([M-H]^-) The calculated value of m/z of (b) was 270.1, and the found value was 269.9.

And 4, step 4: 2-methyl-3- (propylsulfonylamino) benzoic acid

The process is as follows: with 2 equivalents of NaOHGP acThe second part of (a) produces the product.

Yield: 1.2g, 4.5mmol, 86% (white solid).

TLC：PE/EtOAc 50％

¹H NMR(DMSO-d₆,200MHz,ppm):δ12.99(s,1H),9.20(s,1H),7.61(d,J＝7.4Hz, 1H),7.43(d,J＝7.9Hz,1H),7.27(t,J＝7.7Hz,1H),3.14–3.00(m,2H),2.46(s,3H), 1.87–1.62(m,2H),0.98(t,J＝7.4Hz,3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ169.0, 136.5,134.82(s),133.4,129.6,127.5,126.0,53.8,16.9,15.6,12.7.TLC-MS:C₁₁H₁₅NO₄S ([M-H]^-) Calculated value of (2) m/z is 256.1, found value is 225.9.

And 5: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2-methylphenyl) propane Alkane-1-sulfonamides

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 65mg, 140. mu. mol, 53% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.81(s,1H),9.25(s,1H),8.67(d,J＝2.1Hz, 1H),8.54(s,1H),7.85(d,J＝2.2Hz,1H),7.75(d,J＝8.5Hz,2H),7.55(d,J＝8.4Hz,2H), 7.44(t,J＝7.4Hz,1H),7.38–7.24(m,2H),3.15–3.09(m,2H),2.25(s,3H),1.76(dq, J＝15.4,7.7Hz,2H),0.99(t,J＝7.4Hz,3H).¹³C NMR(DMSO-d₆,101Hz,ppm):δ191.6, 168.9,148.8,143.4,141.9,137.2,136.4,132.4,131.2,129.7,129.0,128.8,127.2,127.2, 126.0,124.9,118.0,115.4,53.8,16.9,15.1,12.6.TLC-MS:C₂₄H₂₂ClN₃O₃S([M-H]^-) Calculated value of (2) m/z is 466.1, found value is 466.1.

Example 26: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -4-methylphenyl) Propane-1-sulfonamides

Step 1: 2-methyl-5-nitrobenzoic acid methyl ester

The process is as follows: according to the followingGP aaThe title compound was obtained.

Yield: 1.0g, 5.4mmol, 97% (white solid).

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ8.52(d,J＝2.4Hz,1H),8.29(dd,J＝8.5, 2.6Hz,1H),7.62(d,J＝8.5Hz,1H),3.88(s,3H),2.62(s,3H).¹³C NMR(DMSO-d₆,50Hz, ppm):δ165.5,147.2,145.5,133.2,130.3,126.3,124.7,52.5,21.1。

Step 2: 5-amino-2-methylbenzoic acid methyl ester

The process is as follows: according toGP abTo obtain the title compoundA compound (I) is provided.

Yield: 0.9g, 5.3mmol, 99% (beige oil).

TLC：PE/EtOAc 25％

And step 3: 2-methyl-5- (propylsulfonylamino) benzoic acid methyl ester

The process is as follows: methyl 5-amino-2-methylbenzoate (914mg, 5.5mmol, 1 eq) was dissolved in DCM (0.25 m), pyridine (980. mu.l, 12.2mmol, 2.2 eq) was added and the solution was treated with propane-1-sulfonyl chloride (1.4ml, 12.2mmol, 2.2 eq). The resulting solution was refluxed overnight and then cooled to room temperature. Water was added to quench the reaction, the mixture was extracted with EtOAc, and the combined organic layers were extracted with Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (SiO)₂nHex/EtOAc 20%) was purified.

Yield: 1.4g, 5.1mmol, 93% (colorless oil).

TLC：PE/EtOAc 25％

¹H NMR(CDCl₃,200MHz,ppm):δ7.74(d,J＝2.5Hz,1H),7.35(dd,J＝8.2,2.5Hz, 1H),7.23(t,J＝6.7Hz,1H),7.09(s,1H),3.89(s,3H),3.11–3.00(m,2H),2.55(s,3H), 1.96–1.74(m,2H),1.00(t,J＝7.4Hz,3H).¹³C NMR(CDCl₃,50Hz,ppm):δ167.5,137.2, 134.8,133.1,130.7,124.5,122.9,53.4,52.3,21.2,17.3,13.0.TLC-MS:C₁₂H₁₇NO₄S ([M-H]^-) Calculated value of (2) m/z is 270.1, found value is 269.8.

And 4, step 4: 2-methyl-5- (propylsulfonylamino) benzoic acid

The process is as follows: with 2 equivalents of NaOHGP acThe product is obtained in the second part of (1).

Yield: 1.0g, 4.0mmol, 79% (white solid).

TLC：PE/EtOAc 50％

¹H NMR(DMSO-d₆,200MHz,ppm):δ12.92(s,1H),9.82(s,1H),7.69(d,J＝2.0Hz, 1H),7.36–7.12(m,2H),3.09–2.94(m,2H),2.45(s,3H),1.78–1.54(m,2H),0.92(t, J＝7.4Hz,3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ168.2,136.2,134.3,132.5,131.2,122.9, 121.3,52.3,20.6,16.8,12.5.TLC-MS:C₁₁H₁₅NO₄S([M-H]^-) Calculated value of (2) m/z is 256.1, found value is 225.9.

And 5: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -4-methylphenyl) propane Alkane-1-sulfonamides

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 99mg, 211. mu. mol, 80% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.83(s,1H),9.83(s,1H),8.68(d,J＝1.9Hz, 1H),8.63(s,1H),7.91(d,J＝2.6Hz,1H),7.77(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H), 7.36–7.24(m,3H),3.11–3.03(m,2H),2.25(s,3H),1.74–1.62(m,2H),0.93(t,J＝7.4 Hz,3H).¹³C NMR(DMSO-d₆,101Hz,ppm):δ191.2,148.8,143.5,140.4,137.2,135.7, 132.4,131.7,130.6,129.8,129.0,128.8,127.4,121.0,119.1,118.1,115.1,52.4,18.46,16.8, 12.5.TLC-MS:C₂₄H₂₂ClN₃O₃S([M-H]^-) Calculated value of (2) m/z is 466.1, found value is 466.1.

Example 27: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2-fluorophenyl) propanes Alkane-1-sulfonamides

Step 1: 2-fluoro-3-nitrobenzoic acid methyl ester

The process is as follows: according toGP aaThe title compound was obtained.

Yield: 1.1g, 5.4mmol, 99% (light yellow solid).

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ8.37(ddd,J＝8.7,7.0,1.8Hz,1H),8.22(ddd, J＝8.2,6.4,1.8Hz,1H),7.55(td,J＝8.2,1.2Hz,1H),3.90(s,3H).¹³C NMR(DMSO-d₆, 50Hz,ppm):δ162.6(d,J＝3.2Hz),153.7(d,J＝274.1Hz),138.3(d,J＝8.9Hz),137.1(d, J＝1.8Hz),130.4(d,J＝2.0Hz),125.0(d,J＝5.4Hz),120.7(d,J＝9.7Hz),52.9。

Step 2: 3-amino-2-fluorobenzoic acid methyl ester

The process is as follows: according toGP abThe title compound was obtained.

Yield: 0.9g, 5.3mmol, 99% (brown oil).

TLC：PE/EtOAc 25％

And step 3: 2-fluoro-3- (propylsulfonylamino) benzoic acid

The process is as follows: according toGP acThe title compound was obtained.

Yield: after 2 steps 754mg, 2.9mmol, 55% (white solid).

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ13.39(s,1H),9.78(s,1H),7.72–7.56(m,2H), 7.26(t,J＝8.0Hz,1H),3.16–3.04(m,2H),1.86–1.62(m,2H),0.96(t,J＝7.4Hz,3H). ¹³C NMR(DMSO-d₆,50Hz,ppm):δ164.8(d,J＝2.9Hz),154.5(d,J＝258.9Hz),130.3 (d,J＝1.8Hz),128.3,126.3(d,J＝13.4Hz),124.3(d,J＝4.9Hz),120.3(d,J＝9.6Hz), 53.8,16.9,12.6.TLC-MS:C₁₀H₁₂FNO₄S([M-H]^-) The calculated value of m/z of (2) is 260.5, and the found value is 260.5.

And 4, step 4: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2-fluorophenyl) propane- 1-sulfonamides

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 84mg, 178. mu. mol, 68% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.88(s,1H),9.79(s,1H),8.69(d,J＝2.2Hz, 1H),8.66(d,J＝2.1Hz,1H),8.05(s,1H),7.77(d,J＝8.5Hz,2H),7.60(td,J＝7.9,1.5Hz, 1H),7.56(d,J＝8.5Hz,2H),7.47–7.41(m,1H),7.33(t,J＝7.8Hz,1H),3.15(dd,J＝8.6, 6.7Hz,2H),1.83–1.69(m,2H),0.97(t,J＝7.4Hz,3H).¹³C NMR(DMSO-d₆,101Hz, ppm):δ185.5,152.0(d,J＝249.8Hz),148.8,143.6,137.8,137.1,132.4,129.9,129.0,128.9, 128.8,127.8,127.2,126.1(d,J＝2.0Hz),125.8(d,J＝13.1Hz),124.6(d,J＝4.0Hz),117.9, 114.9,53.8,16.8,12.5.TLC-MS:C₂₃H₁₉ClFN₃O₃S([M-H]^-) The calculated value of m/z of (b) is 470.1, and the found value is 470.1.

Example 28: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -4-fluorophenyl) propanes Alkane-1-sulfonamides

Step 1: 3-butyrylamino (butyrylamido) -2, 6-difluorobenzoic acid

The process is as follows: butyryl chloride was synthesized in situ using butyric acid (1.1 eq), oxalyl chloride (1.05 eq) and DMF (catalyst) as followsGP acThe title compound was obtained.

Yield: after 2 steps 646mg, 2.7mmol, 85% (beige solid).

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ13.87(s,1H),9.75(s,1H),7.87(td,J＝8.9, 6.1Hz,1H),7.15(td,J＝9.2,1.6Hz,1H),2.33(t,J＝7.2Hz,2H),1.72–1.49(m,2H), 0.91(t,J＝7.4Hz,3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ172.1,162.4,156.0(dd,J＝ 203.4,6.6Hz),151.0(dd,J＝207.5,6.6Hz),127.7(dd,J＝10.2,3.2Hz),123.5(dd,J＝ 12.4,3.8Hz),112.7(dd,J＝21.3,18.9Hz),111.9(dd,J＝22.3,3.9Hz),37.9,18.9,13.9。

Step 2: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorophenyl) butan Amides of carboxylic acids

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 46mg, 100. mu. mol, 38% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.01(s,1H),9.80(s,1H),8.71(d,J＝1.7Hz, 1H),8.65(s,1H),8.21(s,1H),7.99(dd,J＝14.8,8.6Hz,1H),7.79(d,J＝8.4Hz,2H),7.56 (d,J＝8.4Hz,2H),7.23(t,J＝8.7Hz,1H),2.36(t,J＝7.2Hz,2H),1.67–1.55(m,2H), 0.91(t,J＝7.3Hz,3H).¹³C NMR(DMSO-d₆,101Hz,ppm):δ180.9,171.6,154.61(dd,J＝ 244.8,5.5Hz),150.4(dd,J＝249.4,6.5Hz),148.9,143.8,138.6,137.0,132.5,130.2,129.0, 128.9,127.1,126.1(dd,J＝6.4,2.6Hz),123.2(dd,J＝12.4,3.4Hz),117.7(dd,J＝19.8, 17.6Hz),117.5,115.7,111.5(dd,J＝22.1,2.6Hz),37.5,18.5,13.5.TLC-MS: C₂₄H₁₈ClF₂N₃O₂([M-H]^-) The calculated value of (b) is 452.1, and the found value is 452.1.

Example 29: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -4-fluorophenyl) propanes Alkane-1-sulfonamides

Step 1: 2-fluoro-5-nitrobenzoic acid methyl ester

The process is as follows: according toGP aaThe title compound was obtained.

Yield: 1.1g, 5.4mmol, 99% (light yellow solid).

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ8.63–8.57(m,1H),8.57–8.47(m,1H),7.73 –7.59(m,1H),3.91(s,3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ164.2(d,J＝267.8Hz), 162.2(d,J＝4.0Hz),143.7(d,J＝3.3Hz),130.3(d,J＝11.6Hz),127.4(d,J＝3.2Hz), 119.2(d,J＝12.5Hz),119.1(d,J＝25.0Hz),53.0。

Step 2: 5-amino-2-fluorobenzoic acid methyl ester

The process is as follows: according toGP abThe title compound was obtained.

Yield: 0.9g, 5.3mmol, 99% (brown oil).

TLC：PE/EtOAc 25％

And step 3: 2-fluoro-5- (propylsulfonylamino) benzoic acid

The process is as follows: according toGP acThe title compound was obtained.

Yield: after 2 steps 777mg, 3.4mmol, 55% (white solid).

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ13.38(s,1H),9.94(s,1H),7.70(dd,J＝6.2, 2.5Hz,1H),7.49–7.37(m,1H),7.28(t,J＝9.5Hz,1H),3.12–2.96(m,2H),1.78–1.54 (m,2H),0.92(t,J＝7.3Hz,3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ164.7(d,J＝3.4Hz), 157.7(d,J＝253.8Hz),134.5(d,J＝3.1Hz),125.9(d,J＝9.0Hz),122.6,119.8(d,J＝11.6 Hz),118.0(d,J＝24.1Hz),52.4,16.8,12.5.TLC-MS:C₁₀H₁₂FNO₄S([M-H]^-) The calculated value of m/z of (2) is 260.1, and the found value is 260.1.

And 4, step 4: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -4-fluorophenyl) propane- 1-sulfonamidesThe process is as follows: according toGP aeThe title compound was obtained.

Yield: 88mg, 186. mu. mol, 71% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.92(d,J＝1.5Hz,1H),9.96(s,1H),8.69(s, 1H),8.68(s,1H),8.12(s,1H),7.78(d,J＝8.5Hz,2H),7.57(d,J＝8.4Hz,2H),7.46–7.33 (m,3H),3.15–3.07(m,2H),1.76–1.63(m,2H),0.95(t,J＝7.4Hz,3H).¹³C NMR (DMSO-d₆,101Hz,ppm):δ185.5,155.3(d,J＝245.2Hz),148.8,143.6,137.9,137.1,134.6, 132.4,130.0,129.0,128.8,128.5(d,J＝17.4Hz),127.3,123.7(d,J＝8.1Hz),121.0(d,J＝ 3.1Hz),118.0,117.3(d,J＝23.4Hz),114.8,52.5,16.8,12.5.TLC-MS:C₂₃H₁₉ClFN₃O₃S ([M-H]^-) The calculated value of (b) is 470.1, and the found value is 470.0.

Example 30: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorobenzene Yl) Hexane-1-sulfonamide

Step 1: 2, 6-difluoro-3- (hexylsulfonylamino) benzoic acid

The process is as follows: according toGP acThe title compound was obtained.

Yield: after 2 steps 237mg, 738. mu. mol, 70% (off-white solid).

TLC：PE/EtOAc 25％

TLC-MS:C₁₂H₁₆F₂NO₂S^·([M-CHO₂]^·-) Calculated value of (2) m/z is 276.1, found value is 275.9.

Step 2: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorophenyl) hexane Alkane-1-sulfonamides

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 88mg, 165. mu. mol, 63% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.04(s,1H),9.78(s,1H),8.71(d,J＝2.1Hz, 1H),8.63(s,1H),8.25(d,J＝1.8Hz,1H),7.79(d,J＝8.4Hz,2H),7.66–7.50(m,3H), 7.29(t,J＝8.7Hz,1H),3.18–3.07(m,2H),1.76–1.63(m,2H),1.40–1.27(m,2H),1.26 –1.15(m,4H),0.79(t,J＝6.7Hz,3H).¹³C NMR(DMSO-d₆,101Hz,ppm):δ180.6,156.0 (dd,J＝247.0,6.9Hz),152.3(dd,J＝249.9,8.3Hz),149.0,143.9,138.7,137.0,132.5,130.2, 129.1,128.9,128.7(m),127.0,121.9(dd,J＝13.8,3.5Hz),118.1(dd,J＝36.3,12.7Hz), 117.5,115.7,112.3(dd,J＝22.8,3.5Hz),51.9,30.6,27.0,23.0,21.7,13.7.TLC-MS: C₂₆H₂₄ClF₂N₃O₃S([M-H]^-) The calculated value of m/z of (2) is 530.1, and the found value is 530.0.

Example 31: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorobenzene 3-methylbutane-1-sulfonamide

Step 1: 2, 6-difluoro-3- ((3-methylbutyl) sulfonylamino) benzoic acid

The process is as follows: according to the followingGP acThe title compound was obtained.

Yield: after 2 steps 171mg, 556. mu. mol, 53% (off-white solid).

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,400MHz,ppm):δ9.76(s,1H),7.54(td,J＝8.9,5.9Hz,1H), 7.20(td,J＝9.0,0.9Hz,1H),3.12–3.05(m,2H),1.70–1.56(m,3H),0.86(d,J＝6.2Hz, 6H).¹³C NMR(DMSO-d₆,101Hz,ppm):δ161.7,156.5(dd,J＝250.9,6.1Hz),153.0(dd, J＝254.2,7.5Hz),129.7(d,J＝10.1Hz),121.9(dd,J＝13.4,3.6Hz),113.0–112.5(m), 112.2(dd,J＝22.7,3.8Hz),50.4,31.7,26.4,21.9.TLC-MS:C₁₂H₁₅F₂NO₄S([M-H]^-) Calculated value of (2) m/z was 306.1, found value was 306.0.

Step 2: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorophenyl) - 3-methylbutane-1-sulfonamide

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 77mg, 149. mu. mol, 57% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.03(s,1H),9.79(s,1H),8.71(d,J＝1.9Hz, 1H),8.64(s,1H),8.26(s,1H),7.79(d,J＝8.4Hz,2H),7.67–7.47(m,3H),7.29(t,J＝8.6 Hz,1H),3.23–3.02(m,2H),1.69–1.51(m,3H),0.83(d,J＝5.7Hz,6H).¹³C NMR (DMSO-d₆,101Hz,ppm):δ180.6,156.0(dd,J＝246.6,6.9Hz),152.3(dd,J＝249.2,8.6 Hz),149.0,143.9,138.8,137.0,132.5,130.2,129.0,128.9,128.7(d,J＝11.9Hz),127.0, 121.9(dd,J＝12.9,3.1Hz),118.1(dd,J＝24.8,23.0Hz),117.4,115.7,112.3(dd,J＝23.0, 3.1Hz),50.2,31.6,26.4,21.9.TLC-MS:C₂₅H₂₂ClF₂N₃O₃S([M-H]^-) The calculated value of (b) is 516.1, and the found value is 516.0.

Example 32: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorobenzene 2-methoxyethane-1-sulfonamides

Step 1: 2, 6-difluoro-3- ((2-methoxyethyl) sulfonamido) benzoic acid

The process is as follows: according toGP acThe title compound was obtained.

Yield: after 2 steps 79mg, 268. mu. mol, 25% (white solid).

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,400MHz,ppm):δ9.78(s,1H),7.55(td,J＝8.8,6.0Hz,1H), 7.20(t,J＝9.0Hz,1H),3.68(t,J＝6.0Hz,2H),3.40(t,J＝6.0Hz,2H),3.19(s,3H).¹³C NMR(DMSO-d₆,101Hz,ppm):δ161.8,156.4(dd,J＝251.0,6.2Hz),152.9(dd,J＝254.4, 7.5Hz),129.3(dd,J＝10.1,1.8Hz),121.9(dd,J＝13.3,3.7Hz),112.7(dd,J＝21.3,19.4 Hz),112.1(dd,J＝22.5,3.9Hz),65.7,57.9,52.1.TLC-MS:C₁₀H₁₁F₂NO₅S([M-H]^-) Calculated value of (2) m/z is 295.0, found value is 295.0.

Step 2: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorophenyl) - 2-methoxyethane-1-sulfonamides

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 59mg, 117. mu. mol, 67% (white solid).

TLC:：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.03(s,1H),9.83(s,1H),8.71(d,J＝2.2Hz, 1H),8.65(s,1H),8.24(s,1H),7.79(d,J＝8.5Hz,2H),7.65–7.52(m,3H),7.28(t,J＝ 8.7Hz,1H),3.70(t,J＝6.1Hz,2H),3.45(t,J＝6.1Hz,2H),3.20(s,3H).¹³C NMR (DMSO-d₆,101Hz,ppm):δ180.6,155.9(dd,J＝246.3,7.1Hz),152.2(dd,J＝249.0,7.7 Hz),149.0,144.0,138.7,137.0,132.5,130.2,129.0,128.9,128.3(d,J＝8.7Hz),127.0, 121.9(dd,J＝13.5,3.5Hz),118.1(dd,J＝24.2,22.3Hz),117.5,115.7,112.2(dd,J＝22.6, 3.5Hz),65.7,57.9,51.8.TLC-MS:C₂₃H₁₈ClF₂N₃O₄S([M-H]^-) Calculated value of (2) is 504.1, found value is 503.9.

Example 33: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorobenzene Yl) Pentane-1-sulfonamides

Step 1: 2, 6-difluoro-3- (pentylsulfonamido) benzoic acid

The process is as follows: according toGP acThe title compound was obtained.

Yield: after 2 steps 236mg, 768. mu. mol, 73% (white solid).

TLC：PE/EtOAc 25％

TLC-MS:C₁₂H₁₅F₂NO₄S([M-H]^-) Calculated value of (2) m/z was 306.1, found value was 306.0.

Step 2: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluorophenyl) pentanes Alkane-1-sulfonamides

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 73mg, 141. mu. mol, 54% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.03(s,1H),9.78(s,1H),8.71(d,J＝1.8Hz, 1H),8.63(s,1H),8.25(s,1H),7.79(d,J＝8.4Hz,2H),7.62-7.55(m,3H),7.29(t,J＝8.7 Hz,1H),3.17–3.09(m,2H),1.71(dt,J＝15.1,7.5Hz,2H),1.40–1.20(m,4H),0.81(t,J ＝7.1Hz,3H).¹³C NMR(DMSO-d₆,101Hz,ppm):δ180.6,156.0(dd,J＝246.6,6.8Hz), 152.3(dd,J＝249.6,8.4Hz),149.0,143.9,138.7,137.0,132.5,130.2,129.0,128.9,128.9– 128.5(m),127.0,121.9(dd,J＝13.6,3.4Hz),118.5–117.8(m),117.5,115.7,112.3(dd,J＝ 22.9,3.5Hz),51.8,29.5,22.7,21.5,13.5.TLC-MS:C₂₅H₂₂ClF₂N₃O₃S([M-H]^-) The calculated value of m/z of (b) is 516.1, and the found value is 516.2.

Example 34: n- (3- (5- (benzo [ d ]))][1,3]Dioxolen-5-yl) -1H-pyrrolo [2,3-b]Pyridine (II) Pyridine-3-carbonyl) -2, 4-difluorophenyl) methanesulfonamide

Step 1: 2-fluoro-3- (methylsulfonylamino) benzoic acid

The process is as follows: according toGP acThe title compound was obtained.

Yield: after 2 steps, 1.82g, 7.8mmol, 72% (white solid).

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ13.36(s,1H),9.76(s,1H),7.65(ddd,J＝15.0, 8.2,1.2Hz,2H),7.27(t,J＝8.0Hz,1H),3.05(s,3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ 164.8(d,J＝2.8Hz),154.7(d,J＝259.4Hz),130.5,128.6,126.3(d,J＝13.4Hz),124.4(d, J＝4.8Hz),120.4(d,J＝9.5Hz),40.5(d,J＝1.0Hz).TLC-MS:C₈H₈FNO₄S([M-H]^-) The calculated value of m/z of (2) was 232.0, and the found value was 231.9.

Step 2: n- (3- (5-bromo-1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2-fluorophenyl) methanesulfonamide

The process is as follows: according toGP aeThe title compound was obtained.

Yield: 1.19g, 2.9mmol, 82% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,200MHz,ppm):δ12.98(s,1H),9.77(s,1H),8.61(d,J＝2.1Hz, 1H),8.47(d,J＝2.1Hz,1H),8.09(s,1H),7.60(dd,J＝7.9,6.4Hz,1H),7.51–7.25(m, 2H),3.10(s,3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ185.5,152.2(d,J＝250.5Hz), 147.6,145.0,138.5(d,J＝1.5Hz),131.3,128.7(d,J＝15.1Hz),128.1,126.4(d,J＝2.7 Hz),125.8(d,J＝13.4Hz),124.7(d,J＝4.3Hz),119.6,114.2,114.0.TLC-MS: C₁₅H₁₁BrFN₃O₃S([M-H]^-) Calculated value of (b) is 410.0, found value is 409.9.

And 3, step 3: n- (3- (5- (benzo [ d ]))][1,3]Dioxolen-5-yl) -1H-pyrrolo [2,3-b]Pyridine-3- Carbonyl) -2-fluorophenyl) methanesulfonamide

The process is as follows: according toGP adThe title compound was obtained.

Yield: 42mg, 93. mu. mol, 45% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.81(s,1H),9.79(s,1H),8.61(d,J＝2.0Hz, 1H),8.58(d,J＝1.9Hz,1H),8.02(s,1H),7.59(t,J＝7.2Hz,1H),7.44(t,J＝6.1Hz,1H), 7.34(t,J＝7.8Hz,1H),7.30(d,J＝1.3Hz,1H),7.18(dd,J＝8.0,1.5Hz,1H),7.04(d, J＝8.0Hz,1H),6.08(s,2H),3.09(s,3H).TLC-MS:C₂₂H₁₆FN₃O₅S([M-H]^-) The calculated value of (b) is 452.1, and the found value is 452.1.

Example 35: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2-fluorophenyl) methyl ester Alkanesulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 27mg, 61. mu. mol, 31% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.88(s,1H),9.79(s,1H),8.68(dd,J＝7.3, 2.2Hz,2H),8.06(d,J＝1.6Hz,1H),7.77(d,J＝8.6Hz,2H),7.63–7.53(m,3H),7.49– 7.41(m,1H),7.34(t,J＝7.8Hz,1H),3.10(s,3H).TLC-MS:C₂₁H₁₅ClFN₃O₃S([M-H]^-) The calculated value of (b) is 442.1, and the found value is 442.0.

Example 36: n- (3- (5- (2, 3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) -1H-pyrrolo [2, 3-b]pyridine-3-carbonyl) -2-fluorophenyl) methanesulfonamide

The process is as follows: according toGP adThe title compound was obtained.

Yield: 39mg, 83. mu. mol, 43% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.80(s,1H),9.79(s,1H),8.60(d,J＝2.2Hz, 1H),8.56(d,J＝2.2Hz,1H),8.01(s,1H),7.59(td,J＝7.8,1.5Hz,1H),7.46–7.41(m, 1H),7.34(t,J＝7.8Hz,1H),7.22–7.13(m,2H),6.98(d,J＝8.2Hz,1H),4.29(s,4H), 3.09(s,3H).TLC-MS:C₂₃H₁₈FN₃O₅S([M-H]^-) Calculated value of (2) m/z is 466.1, found value is 466.1.

Example 37: n- (2-fluoro-3- (5- (4-fluoro-2-methylphenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) Phenyl) methanesulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 41mg, 93. mu. mol, 48% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.87(s,1H),9.78(s,1H),8.36(d,J＝2.1Hz, 1H),8.34(d,J＝2.1Hz,1H),8.06(d,J＝1.4Hz,1H),7.59(td,J＝7.8,1.6Hz,1H),7.47– 7.41(m,1H),7.34(dd,J＝8.3,6.1Hz,2H),7.22(dd,J＝10.1,2.5Hz,1H),7.13(td,J＝8.5, 2.6Hz,1H),3.09(s,3H),2.26(s,3H).TLC-MS:C₂₂H₁₇F₂N₃O₃S([M-H]^-) The calculated value of m/z of (b) is 440.1, and the found value is 440.1.

Example 38: n- (3- (5- (2-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2-fluorophenyl) methyl ester Alkanesulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 32mg, 72. mu. mol, 46% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ12.93(s,1H),9.79(s,1H),8.52(d,J＝2.0Hz, 1H),8.44(d,J＝2.1Hz,1H),8.10(s,1H),7.66–7.42(m,6H),7.34(t,J＝7.8Hz,1H), 3.09(s,3H).TLC-MS:C₂₁H₁₅ClFN₃O₃S([M-H]^-) The calculated value of m/z was 442.1, and the found value was 442.1.

Example 39: n- (3- (5- (2-chloro-4-methoxyphenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, pyridine-3-carbonyl, 4-difluorophenyl) propane-1-sulfonamide

The process is as follows: according toGP adThe title compound was obtained.

Yield: 53mg, 102. mu. mol, 59% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,300MHz,ppm):δ13.03(d,J＝1.7Hz,1H),9.77(s,1H),8.44(s, 1H),8.41(d,J＝2.0Hz,1H),8.25(d,J＝2.1Hz,1H),7.58(td,J＝9.0,6.0Hz,1H),7.47(d, J＝8.5Hz,1H),7.28(t,J＝8.4Hz,1H),7.21(d,J＝2.5Hz,1H),7.06(dd,J＝8.6,2.5Hz, 1H),3.85(s,3H),3.18–3.06(m,2H),1.82–1.66(m,2H),0.96(t,J＝7.4Hz,3H). TLC-MS:C₂₄H₂₀ClF₂N₃O₄S([M-H]^-) Calculated value of (2) m/z is 518.1, found value is 518.1.

Example 40: n- (3- (5- (2-chloro-4-fluorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-bis Fluorophenyl) propane-1-sulfonamide

The process is as follows: according toGP adThe title compound was obtained.

Yield: 36mg, 71. mu. mol, 41% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,300MHz,ppm):δ13.07(s,1H),9.77(s,1H),8.47(s,1H),8.43 (d,J＝2.1Hz,1H),8.27(s,1H),7.67–7.52(m,3H),7.37(td,J＝8.5,2.6Hz,1H),7.28(td, J＝8.9,1.3Hz,1H),3.18–2.93(m,2H),1.83–1.64(m,2H),0.96(t,J＝7.4Hz,3H). TLC-MS:C₂₃H₁₇ClF₃N₃O₃S([M-H]^-) The calculated value of (b) is 506.1, and the found value is 505.9.

Example 41: n- (3- (5- (2, 4-dichlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) -2, 4-difluoro Phenyl) propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 25mg, 48. mu. mol, 27% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,300MHz,ppm):δ13.08(s,1H),9.77(s,1H),8.48(s,1H),8.45 (d,J＝1.9Hz,1H),8.28(s,1H),7.80(d,J＝1.2Hz,1H),7.59(m,3H),7.28(t,J＝8.4Hz, 1H),3.18–3.04(m,2H),1.81–1.65(m,2H),0.96(t,J＝7.4Hz,3H).TLC-MS: C₂₃H₁₇Cl₂F₂N₃O₃S([M-H]^-) Calculated value of (2) m/z is 522.0, found value is 521.9.

Example 42: n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b) ]Pyridine-3-carbonyl) -4-methylphenyl) Propane-1-sulfonamides

Step 1: 2-chloro-3-nitrobenzoic acid methyl ester

The process is as follows: according toGP aaThe title compound was obtained.

Yield: 1.06g, 4.9mmol, quantitative (light yellow solid).

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ8.21(dd,J＝8.0,1.5Hz,1H),8.06(dd,J＝7.8, 1.5Hz,1H),7.71(t,J＝7.9Hz,1H),3.91(s,3H).¹³C NMR(DMSO-d₆,50Hz,ppm):δ 164.4,149.4,133.7,132.7,128.9,127.6,123.0,53.1。

Step 2: 3-amino-2-chlorobenzoic acid methyl ester

The process is as follows: the above ester (1.06g, 4.9mmol, 1 equiv.) and HCl solution (1m, 4.9mL, 1 equiv.) were dissolved in EtOH (0.25m) and heated to reflux. Fine iron powder (302mg, 5.4mmol, 1.1 eq) was added portionwise to the hot solution and the resulting mixture was refluxed until complete consumption of the starting material. The crude mixture was passed through a pad of celite, diluted with EtOAc, and the organic layer was washed with water and brine. The combined organic layers were washed with Na₂SO₄The solvent was removed under reduced pressure and the product was used without further purification.

Yield: 1.06g, 4.8mmol, 98% (brown oil).

TLC：PE/EtOAc 25％

And step 3: 2-chloro-3- (propylsulfonylamino) benzoic acid

The process is as follows: according toGP acThe title compound was obtained.

Yield: after 2 steps, 402mg, 1.5mmol, 61% (off-white solid).

TLC：PE/EtOAc 25％

¹H NMR(DMSO-d₆,200MHz,ppm):δ13.50(s,1H),9.58(s,1H),7.64–7.52(m,2H), 7.40(t,J＝7.8Hz,1H),3.20–3.03(m,2H),1.87–1.63(m,2H),0.97(t,J＝7.4Hz,3H). ¹³C NMR(DMSO-d₆,50Hz,ppm):δ166.9,135.3,133.7,129.3,127.5,127.2,126.5,54.7, 16.9,12.7.TLC-MS:C₁₀H₁₂ClNO₄S([M-H]^-) Calculated value of (2) m/z is 276.0, found value is 275.9.

And 4, step 4: n- (2-chloro-3- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridine-3-carbonyl) phenyl) propane- 1-sulfonamidesThe process is as follows: according to GP aeThe title compound was obtained.

Yield: 59mg, 121. mu. mol, 46% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,300MHz,ppm):δ12.88(s,1H),9.61(s,1H),8.69(d,J＝2.2Hz, 1H),8.53(s,1H),7.95(s,1H),7.76(d,J＝8.5Hz,2H),7.63(dd,J＝8.0,1.6Hz,1H),7.55 (d,J＝8.5Hz,2H),7.49(t,J＝7.8Hz,1H),7.40(dd,J＝7.5,1.5Hz,1H),3.16(dd,J＝8.7, 6.6Hz,2H),1.85–1.68(m,2H),0.97(t,J＝7.4Hz,3H).TLC-MS:C₂₃H₁₉Cl₂N₃O₃S ([M-H]^-) The calculated value of m/z of (2) is 486.1, and the found value is 486.1.

Example 43: n- (3- (5- (6-chlorobenzo [ d ]))][1,3]Dioxolen-5-yl) -1H-pyrrolo [2,3-b] Pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonamide

Step 1: 6-chlorobenzo [ d][1,3]Dioxole-5-ols

The process is as follows: ZrCl was added in sequence to a-78 deg.C cooled solution of N-chlorosuccinimide (967mg, 7.2mmol, 1 equiv) in DCM (0.125m)₄(337mg, 1.5mmol, 0.2 equiv.) and sesamol (1.0g, 7.2mmol, 1 equiv.). The reaction mixture was stirred at room temperature for 130 minutes and saturated NaHCO was used₃And (4) quenching the aqueous solution. The crude product was extracted with DCM and the combined organic layers were washed with brine and over Na₂SO₄And (5) drying. Then, the solvent was removed under reduced pressure and purified by flash chromatography (SiO)₂nHex/EtOAc 10%) purified the product.

Yield: 998mg, 5.8mmol, 80% (white solid).

TLC：PE/EtOAc 25％

¹H NMR(CDCl₃,200MHz,ppm):δ6.77(s,1H),6.57(s,1H),5.92(s,2H),5.22(s, 1H).¹³C NMR(CDCl₃,50Hz,ppm):δ147.6,146.5,141.7,110.3,108.4,101.8,98.3. TLC-MS:C₇H₅ClO₃([M-H]^-) Calculated value of (2) m/z is 171.0, found value is 171.0.

Step 2: 6-chlorobenzo [ d][1,3]Dioxol-5-yl trifluoromethanesulfonate ester

The process is as follows: reacting 6-chlorobenzo [ d][1,3]A solution of dioxol-5-ol (960mg, 5.6mmol, 1 eq) in DCM (0.57m) was cooled to 0 deg.C and iPr was added ₂NH (782. mu.l, 5.6mmol, 1 eq.) and Tf₂O (1.0ml, 6.1mmol, 1.1 equiv.). The mixture was stirred at room temperature until complete consumption of the starting material was observed. Using NaHCO₃The reaction was quenched with aqueous solution (5%), the resulting phases were separated, and the aqueous phase was extracted with DCM. The combined organic layers were washed with Na₂SO₄Dried and the solvent evaporated in vacuo. Flash chromatography (SiO)₂nHex/EtOAc 5%) to yield the purified product.

Yield: 1.1g, 3.7mmol, 67% (light yellow oil).

TLC：PE/EtOAc 10％

¹H NMR(CDCl₃,200MHz,ppm):δ6.92(s,1H),6.82(s,1H),6.07(s,2H)。

And step 3: 2- (6-chlorobenzo [ d ]][1,3]Dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxo Heterocyrocyclopentane borane (dioxaborolane)

The process is as follows: pd (PPh)₃)₂Cl₂(127mg, 181. mu. mol, 0.05 eq.) B₂Pin₂(1.4g, 5.42mmol, 1.5 equiv.), KOAc (1.1g, 10.8mmol, 3 equiv.), and 6-chlorobenzo [ d][1,3]Dioxolen-5-yl trifluoromethanesulfonate (1.1g, 3.6mmol, 1 eq.) was placed in an oven-dried flask under an argon atmosphere. Anhydrous 1, 4-dioxane (0.5m) was added and the mixture was degassed with argon. The reaction mixture was heated to 100 ℃ overnight and then passed through a pad of celite, washing with EtOAc. Flash chromatography (SiO)₂nHex/EtOAc 5%) to yield the purified product.

Yield: 887 mg. 3.1 mmol. 87% (white solid).

TLC：PE/EtOAc 10％

¹H NMR(CDCl₃,200MHz,ppm):δ7.11(s,1H),6.81(s,1H),5.95(s,2H),1.33(s, 12H).¹³C(CDCl₃,50Hz,ppm):δ150.5,146.3,133.1,114.9,110.6,101.8,84.1,83.6,24.9。

And 4, step 4: n- (3- (5- (6-chlorobenzo [ d ]))][1,3]Dioxolen-5-yl) -1H-pyrrolo [2,3-b]Pyridine (II) Pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonamide

The process is as follows: according toGP adThe title compound was obtained.

Yield: 58mg, 109. mu. mol, 50% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,300MHz,ppm):δ13.03(s,1H),9.77(s,1H),8.43(s,1H),8.39 (d,J＝2.1Hz,1H),8.25(d,J＝1.5Hz,1H),7.59(td,J＝9.0,5.9Hz,1H),7.31–7.24(m, 1H),7.24(s,1H),7.14(s,1H),6.15(s,2H),3.18–3.06(m,2H),1.82–1.65(m,2H),0.96(t, J＝7.4Hz,3H).TLC-MS:C₂₄H₁₈ClF₂N₃O₅S([M-H]^-) The calculated value of m/z of (2) was 532.1, and the found value was 532.2.

Example 44:n- (3- (5- (7-chloro-2, 3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) -1H-pyrroles And [2,3-b ]]Pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonamide

Step 1: 2, 3-dihydrobenzo [ b ]][1,4]Dioxin-6-ols

The process is as follows: 2, 3-dihydrobenzo [ b ]][1,4]Dioxin-6-carbaldehyde (2g, 12.2mmol, 1 eq.) was placed in a mortar, mCPBA (4.5g, 18.3mmol, 1.5 eq.) was added, and the solids were mixed with a pestle. The resulting paste was left at room temperature for 5 minutes and then treated with NaOH (in H)₂10% in O). The solution was taken up in Et₂O wash, adjust to pH 7 with HCl (2m) and extract with DCM. The combined organic layers were washed with Na₂SO₄After drying, the solvent is evaporated and purified by flash chromatography (SiO)₂nHex/EtOAc/AcoH 79/20/1).

Yield: 1.7g, 11.2mmol, 92% (off-white solid).

TLC：PE/EtOAc/AcOH 74/25/1

¹H NMR(CDCl₃,200MHz,ppm):δ6.72(dd,J＝8.6,0.4Hz,1H),6.40(dd,J＝2.9, 0.4Hz,1H),6.33(dd,J＝8.6,2.9Hz,1H),4.32–4.14(m,4H),4.00(s,1H).¹³C NMR (CDCl₃,50Hz,ppm):δ150.1,144.0,137.7,117.7,108.5,104.4,64.7,64.2。

Step 2: 7-chloro-2, 3-dihydrobenzo [ b ]][1,4]Dioxin-6-ols

The process is as follows: ZrCl was added in sequence to a-78 deg.C cooled solution of N-chlorosuccinimide (1.9g, 14.0mmol, 1.05 equiv) in DCM (0.125m)₄(619mg, 2.7mmol, 0.2 equiv.) and 2, 3-dihydrobenzo [ b ]][1,4] Dioxins (I) in the form of dioxins-6-ol (2.0g, 13.3mmol, 1 equiv). The reaction mixture was stirred at room temperature for 180 minutes and saturated NaHCO was used₃And (4) quenching the aqueous solution. The crude product was extracted with DCM and the combined organic layers were washed with brine and over Na₂SO₄And (5) drying. Then, the solvent was removed under reduced pressure and purified by flash chromatography (SiO)₂nHex/EtOAc 10%) purified the product.

Yield: 1.4g, 7.3mmol, 55% (light green oil).

TLC：PE/EtOAc 25％

¹H NMR(CDCl₃,200MHz,ppm):δ6.83(s,1H),6.55(s,1H),5.21(s,1H),4.27–4.14 (m,4H).¹³CNMR(CDCl₃,50Hz,ppm):δ145.9,143.4,137.8,116.8,111.5,104.8,64.6, 64.2。

And step 3: 7-chloro-2, 3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl trifluoromethanesulfonate ester

The process is as follows: reacting 7-chloro-2, 3-dihydrobenzo [ b ]][1,4]A solution of dioxin-6-ol (1.3mg, 7.1mmol, 1 eq.) in DCM (0.57m) was cooled to 0 deg.C and iPr was added₂NH(994μl，7.1mmol，1Equivalent) and Tf₂O (1.3ml, 7.8mmol, 1.1 equiv.). The mixture was stirred at room temperature until complete consumption of the starting material was observed. Using NaHCO₃The reaction was quenched with aqueous solution (5%), the resulting phases were separated, and the aqueous phase was extracted with DCM. The combined organic layers were washed with Na₂SO₄Dried and the solvent evaporated in vacuo. Flash chromatography (SiO) ₂nHex/EtOAc 5%) to give the purified product.

Yield: 1.5g, 4.6mmol, 64% (colorless oil).

TLC:PE/EtOAc 10％

¹H NMR(CDCl₃,200MHz,ppm):δ7.00(s,1H),6.89(s,1H),4.27(s,4H)。

And 4, step 4: 2- (7-chloro-2, 3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) -4,4,5, 5-tetramethyl- 1,3, 2-dioxaborolane

The process is as follows: pd (PPh) under argon atmosphere₃)₂Cl₂(156mg, 223. mu. mol, 0.05 eq.) B₂Pin₂(1.7g, 6.7mmol, 1.5 equiv.), KOAc (1.3g, 13.4mmol, 3 equiv.), and 7-chloro-2, 3-dihydrobenzo [ b ]][1,4]Dioxyheterocyclic ring Hexene-6-Yl-trifluoromethane sulfonate (1.4g, 4.5mmol, 1 eq.) was placed in an oven-dried flask. Anhydrous 1, 4-dioxane (0.5m) was added and the mixture was degassed with argon. The reaction mixture was heated to 100 ℃ overnight and then passed through a pad of celite, washing with EtOAc. Flash chromatography (SiO)₂nHex/EtOAc 5%) to yield the purified product.

Yield: 1.2mg, 4.2mmol, 94% (white solid).

TLC:PE/EtOAc 10％

¹H NMR(CDCl₃,200MHz,ppm):δ7.21(s,1H),6.86(s,1H),4.22(s,4H),1.33(s, 12H)。¹³C NMR(CDCl₃,50Hz,ppm):δ146.2,142.0,131.8,125.2,118.3,84.0,64.7,64.2, 24.9。

And 5: n- (3- (5- (7-chloro-2, 3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) -1H-pyrrolo [2,3-b]Pyridine-3-carbonyl) -2, 4-difluorophenyl) Propane-1-sulfonamides

The process is as follows: according toGP adThe title compound was obtained.

Yield: 36mg, 71. mu. mol, 41% (white solid).

TLC：DCM/MeOH 5％

¹H NMR(DMSO-d₆,400MHz,ppm):δ13.02(s,1H),9.77(s,1H),8.43(s,1H),8.39 (d,J＝2.2Hz,1H),8.24(s,1H),7.58(td,J＝9.0,5.9Hz,1H),7.27(td,J＝9.0,1.3Hz,1H), 7.14(s,1H),7.05(s,1H),4.31(s,4H),3.16–3.07(m,2H),1.80–1.67(m,2H),0.96(t, J＝7.4Hz,3H).TLC-MS:C₂₅H₂₀ClF₂N₃O₅S([M-H]^-) The calculated value of (1) m/z was 546.1, and the found value was 546.6.

The compounds given in tables 2 and 3 were prepared according to the general procedure described above:

Table 2:

table 3:

the following compounds were prepared using conventional methods according to the reaction sequence given below:

example 104: n- (3- (2- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -1, 3-dioxa Synthesis of cyclopentan-2-yl) -2, 4-difluorophenyl) propane-1-sulfonamide

Example 105: n- (3- ((5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methyl) -2, 4-bis Synthesis of fluorophenyl) propane-1-sulfonamide

Example 106: n- (5- (4-chlorophenyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -2, 6-difluoro-3-) propyl Synthesis of sulfonamido) benzamides

Synthesis of intermediates E (for example 106) and F (for example 107)

Example 107: 5- (4-chlorophenyl) -N- (2, 6-difluoro-3- (propylsulfonylamino) phenyl) -1H-pyrrolo [2, 3-b]synthesis of pyridine-3-carboxamides

Examples 108 to 110

Synthesis of intermediate C:

example 111: synthesis of N- (4- (5- (4-chlorophenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) thiazol-2-yl) propane-1-sulfonamide

Synthesis of intermediate G

Example 112: synthesis of N- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonimide (sulfonimide)

Example 113: biological activity

Example 113-1: binding assays

Kinomescan using Discovex Corporation, 42501Albrae St.Fremont, CA 94538, USA^TMProfiling Service measures the kinase activity of the compounds of the invention based on a competition binding assay that quantitatively measures the ability of a compound to compete with immobilized, active site-directed ligands. The assay was performed by combining three components: a DNA-tagged kinase; immobilizing a ligand; and a test compound. The ability of the test compound to compete with the immobilized ligand was measured by quantitative PCR of the DNA tag. The technology isThe technique is described in detail in Fabian, M.A. et al.A. small molecule kinase interaction map for clinical kinase inhibitors, Nat.Biotechnol.,23,329-336(2005) and Karaman, M.W. et al.A. quantitative analysis of kinase inhibitor selectivity Nat.Biotechnol., 26,127-132 (2008).

To investigate the affinity for MKK4, MKK7, and JNK1, kinases were produced in HEK-293 cells, followed by DNA labeling for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. Ligand beads were blocked with excess biotin and blocked with blocking buffer (SEABLOCK) ^TM(Pierce),1％BSA,0.05％

20,1mM DTT) to remove unbound ligand and reduce non-specific binding. By mixing kinase, ligand affinity beads and test compound in 1 Xbinding buffer (20% SEABLOCK)^TM,0.17x PBS,0.05％

20,6mM DTT) to assemble a binding reaction. All reactions were performed in polystyrene 96-well plates with a final volume of 0.135 mL. Assay plates were incubated with shaking at room temperature for 1 hour and washed with wash buffer (lx PBS, 0.05%

20) The affinity beads were washed. The beads were then resuspended in elution buffer (lx PBS, 0.05%

20, 0.511M non-biotinylated affinity ligand) and incubated at room temperature for 30 minutes with shaking. The kinase concentration in the eluate was measured by qPCR.

In more than 135 independent experiments spanning 16 months, the mean Z' value and standard deviation for each kinase was calculated for each experiment based on 14 control wells. Average Z' is 0.71.

Efficacy of the test compounds:

compounds were screened at the indicated concentrations and the results of binding interactions were reported as [% control ], where lower numbers indicate stronger binding, i.e. higher potency.

Details regarding the kinases tested are given in table 4 below.

Test compounds were provided as 10mM stock solutions. Test solutions at the indicated final concentrations were prepared in discover x. The results are given in tables 5 to 7 below.

Table 4:

table 5: MKK4 efficacy

*: efficacy derived from [% control ] value (PoC) according to the following classification rules:

table 6: selectivity compared to JNK1

JNK1 PoC 100

Since the PoC value of JNK1 was 100, it is clear that compounds 20 to 43 of the present invention inhibit MKK4 with high selectivity compared to JNK 1.

Table 7: MKK4 potency and selectivity compared to MKK7

JNK1 PoC 100

Table 8: MKK4 potency and selectivity relative to BRaf

JNK1 PoC 100

Example 113-2: functional enzyme assay

(a) Material

Recombinant kinase protein (commercially available)

MEKK2, recombinant, active: ProQinase product #0583-

MKK4, recombination, activation: ProQinase product #0948-

MKK4, recombinant, unactivated: ProQinase product #0948-

Substrate proteins

Casein (Sigma C-4765)

JNK 1K 55R/K56R, recombinant, inactive: proqinase product #0524-

(b) Method of producing a composite material

(b-1) MEKK 2-dependent MKK4 activation

MKK4 (unactivated) and MEKK2 (active) were incubated in the presence of compound or vehicle and 20. mu.M ATP at 30 ℃ for 30 min at a ratio of 10:1(w/w), corresponding to a molar ratio of 20: 1. The activation step was performed at 50mM HEPES pH 7.5, 50mM NaCl, 3.8mM MgCl₂2.5mM DTT, 10% (v/v) glycerol. The final DMSO concentration was 1%. The activation mixture was pipetted in the following order:

2.5. mu.l of compound in 4% DMSO

2.5. mu.l ATP/MgCl2 mixture

5 μ l of premixed kinase solution MKK4: MEKK 210: 1(w/w)

The protein concentration in the activation mixture was 1. mu.M MKK4 and 50nM MEKK 2.

(b-2) protein kinase assay

A radioactive protein kinase assay is used to measure the kinase activity of each protein kinase. All kinase assays were performed in 96-well polypropylene plates. After stopping the reaction, the assay mixture was transferred to a 96-well MSFC filter plate (Millipore). The reaction mixture was passed through a filter by suction, with 150mM H₃PO₄The membrane was washed 3 times, once with ethanol, dried and the liquid scintillation cocktail was added. Radioactivity was determined by counting samples in a Microbeta multi-well scintillation counter (Wallac). The reactants were pipetted in the following order:

a) MEKK2-MKK4 activation mix

20. mu.l of Standard assay buffer

10. mu.l of MEKK2-MKK4 activation mixture

5 μ l of radioactive 33P-. gamma. -ATP solution (typically 10)⁶cpm/well)

10. mu.l of substrate solution

b) Single kinase

20. mu.l of Standard assay buffer

5. mu.l of compound in 10% DMSO

20. mu.l enzyme-substrate mixture

10. mu.l of substrate solution

The assay contained 70mM HEPES-NaOH pH 7.5, 3mM MgCl₂、3mM MnCl₂3 μ M Na-orthovanadate, 1.2mM DTT, ATP (variable amount, corresponding to the apparent ATP-Km of the corresponding kinase, see Table 1), [ 2 ] ³³P-gamma-ATP (approximately 8X 10 per well)⁰⁵cpm), protein kinase (variable, see table 1) and substrate (variable, see table below).

Table 1: enzyme, substrate and assay conditions (amount/well)

The reaction mixture was incubated at 30 ℃ for 30 minutes.

Efficacy of the test compounds:

*: from IC according to the following classification rules₅₀Value (PoC) derived potency:

example 113-3: in vivo studies

Animal(s) production

C57BL/6N female mice, purchased from Charles River Laboratories, Research Models and Services, Germany GmbH (Sulzfeld), 6 to 9 weeks old, were reared according to the institutional guidelines of the Germany Debine university. All animal experiments were approved by the german legal institution.

Animal experiments and survival studies.

Three experiments were performed with 3, 4, and 6 animals per group. At time point (t ═ 1h), mice were given 30mg/kg of compound (ph4.0) mixed with 2% hydroxymethylcellulose or only by oral gavage. After 1 hour (t ═ 0 hours), all animals were injected intraperitoneally (i.p.) with 0.8 μ g/g mouse body weight of Jo2 antibody (BD Pharmingen, San Diego, CA) diluted with 0.9% NaCl.

Mice were monitored continuously and survival was monitored over 15 minutes. After 24 hours, all surviving animals were sacrificed.

As a result:

the Kaplan-Meier plot illustrates the survival of animals receiving 30mg/kg of the compound according to example 2 or only after i.p. injection of 0.8. mu.g/g of Jo2 antibody. The survival of animals after administration of the compound of example 2 was significantly higher than that of animals used alone. The results are shown in FIG. 1.

Example 113 to 4: cell phenotype analysis

Hepatocyte isolation and culture

Mice were anesthetized and the liver perfused via the intrahepatic vena cava, first with liver perfusion medium (Invitrogen, Darmstadt, Germany) for 15 minutes, and then with Ca at the validation level (Serva Electrophoresis GmbH, Heidelberg, Germany) containing collagenase 400-²⁺Supplemented media Williams E Medium (PAN Biotech, Aidenbach Germany) and collagenase (Serva) perfuse the liver for approximately 15 minutes. The liver was excised and 50g of the hepatocyte suspension was centrifuged for 5 minutes. The supernatant was discarded, and the pellet containing parenchymal cells was collected and washed once with Williams' E medium (PAN Biotech) without collagenase. The hepatocyte suspension was further centrifuged using a two-step Percoll gradient (24% + 50%), 98% pure viable hepatocytes were collected from the pellet, washed once and seeded on collagen (Roche) -coated 12-well plates at a concentration of 2X 10 in HCM medium (Lonza; Germany) supplemented with 5% FCS, glutamine and antibiotics ⁶Individual cells/well.

Isolated primary hepatocytes are incubated with compound supplemented media. The medium was refreshed after 24 hours. Compounds were added to the medium at a concentration of 1 μ M and DMSO was added in equal volumes.

Labelling with BrdU 10. mu.g/ml was achieved overnight (5-bromo-2' -deoxyuridine Sigma B9285-250mg)

BrdU antibody (Abcam catalog number AB6326)

Statistical significance was assessed by student t-test P <0.05, P <0.005 and P < 0.0005.

Counting was performed using ImageJ software 10 hpf/well (high power field).

As a result:

figure 2 shows the percentage of BrdU positive cells after co-incubation of the compounds according to examples 1 and 2 in cultured primary mouse hepatocytes.

Claims (12)

1. A compound selected from the group consisting of:

n- (3- (5- (benzo [ d ] [1,3] dioxol-5-yl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonamide;

n- (2, 4-difluoro-3- (5- (4-fluoro-2-methylphenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) phenyl) propane-1-sulfonamide;

n- (3- (5- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2-fluorophenyl) methanesulfonamide;

n- (2-fluoro-3- (5- (4-fluoro-2-methylphenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) phenyl) methanesulfonamide;

N- (3- (5- (2-chloro-4-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonamide;

n- (3- (5- (7-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonamide;

n- (3- (5- (4-chlorophenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluorophenyl) benzylsulfonamide;

n- (3- (5- (2-chloro-4-hydroxy-phenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonamide;

n- (3- (5- (2-chloro-4-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2-fluorophenyl) methane-1-sulfonamide;

n- (3- (5- (5-chloro-benzo [ d ] [1,3] dioxol-6-yl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2-fluorophenyl) methane-1-sulfonamide;

n- (2-fluoro-3- (5- (4-fluoro-2-methylphenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) phenyl) butanesulfonamide;

n- (2-fluoro-3- (5- (2-chloro-4-methoxyphenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) phenyl) butanesulfonamide;

n- (3- (5- (benzo [ d ] [1,3] dioxol-5-yl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2-fluorophenyl) butane-1-sulfonamide;

n- (3- (5- (2, 3-dihydrobenzo [ d ] [1,3] dioxin-6-yl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2-fluorophenyl) butane-1-sulfonamide;

N- (3- (5- (5-chloro-benzo [ d ] [1,3] dioxol-6-yl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2-fluorophenyl) butane-1-sulfonamide;

n- (3- (5- (7-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2-fluorophenyl) butane-1-sulfonamide; and

n- (3- (5- (2-chloro-4- (methoxymethoxy) phenyl) -1H-pyrrolo [2,3-b ] pyridine-3-carbonyl) -2, 4-difluorophenyl) propane-1-sulfonamide.

2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for selectively inhibiting the protein kinase MKK4 relative to the protein kinases JNK1 and MKK 7.

4. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for promoting liver regeneration or preventing hepatocyte death.

5. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of acute, chronic plus acute or chronic liver disease.

6. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of:

Acute and chronic or chronic plus acute liver disease.

7. The use according to claim 6, wherein the acute and chronic or chronic plus acute liver diseases are acute and chronic viral hepatitis, hepatitis B, hepatitis C, hepatitis E, hepatitis caused by Epstein-Barr virus, cytomegalovirus, herpes simplex virus, all types of autoimmune hepatitis, primary sclerosing hepatitis, alcoholic hepatitis.

8. The use according to claim 6, wherein the acute and chronic or chronic plus acute liver disease is metabolic liver disease; all types of cirrhosis; acute or chronic liver failure; galactosemia, cystic fibrosis, porphyria, ischemic perfusion injury of the liver, posthepatic minor syndrome after liver transplantation, primary sclerosing cholangitis or hepatic encephalopathy, chronic liver disease caused by right heart failure.

9. The use of claim 8, wherein the metabolic liver disease is fatty liver, non-alcoholic steatohepatitis (NASH), Alcoholic Steatohepatitis (ASH), wilson's disease, hemochromatosis, alpha 1-antitrypsin deficiency, glycogen storage disease.

10. The use of claim 9, wherein the fatty liver is non-alcoholic fatty liver disease (NAFL).

11. The use of claim 8, wherein the cirrhosis is primary biliary cirrhosis, ethanol-toxic cirrhosis, cryptogenic cirrhosis.

12. The use according to claim 8, wherein the acute or chronic liver failure is acetaminophen-induced liver failure, α -amanitin-induced liver failure, drug-induced hepatotoxicity and liver failure caused by antibiotics, non-steroidal anti-inflammatory drugs, anticonvulsants, acute liver failure induced by herbal supplements, liver disease and liver failure caused by bulgan syndrome vascular disease, acute liver failure of unknown cause.

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